The oncogenic properties of BKPyV are well-demonstrated in in vitro and in vivo experimental models. The transforming activity has been mapped in the early region of the BKPy genome, which encodes two viral oncoproteins: the large T-antigen (TAg) and the small t-antigen (tAg). These viral products induce alterations in the normal cell cycle, ultimately leading to cell immortalization and neoplastic transformation.
n 2012, the International Agency for Research on Cancer (IARC) evaluated the carcinogenicity of the BK virus (BKPyV), reporting that BKPyV is “possibly carcinogenic to humans
Conclusions:we need more RCTs to ensure carcinogenicity of BKV
This review explores the BKPyV infection from a historical point of view, including biological aspects related to viral entry, tropism, epidemiology and mechanisms potentially involved in BKPyV-mediated human carcinogenesis.
Human polyomaviruses (HPyV), are small DNA viruses classified into the polyomaviridae family.
Thirteen distinct HPyVs have been described to date. Some of these viruses have been found in human tumors, suggesting an etiological relationship with cancer.
There is convincing evidence of an oncogenic role for the Merkel cell polyomavirus (MCPyV). This HPyV has been linked to rare skin cancer, Merkel cell carcinoma (MCC).
In 2012, the International Agency for Research on Cancer (IARC) evaluated the carcinogenicity of the BK virus (BKPyV), reporting that BKPyV is “possibly carcinogenic to humans.” The primary infection most often occurs in early childhood, with a seroprevalence of 65–90% in 5–9 year old children . After the primary infection, BKPyV persists in the kidneys. In immunosuppressed patients, BKPyV causes hemorrhagic cystitis in bone marrow transplant and nephropathy (BKAN) in renal transplant patients . BKPyV genomes also detected in a wide spectrum of normal tissues including liver, stomach, lungs, parathyroid glands, lymph nodes, brain, peripheral blood mononuclear cells, bladder, uterine cervix, vulva, prostate, lips and tongue . The oncogenic properties of BKPyV are well demonstrated in in vitro and in vivo experimental models. The transforming activity has been mapped in the early region of the BKPyV genome, which encodes two viral oncoproteins: the large T-antigen (TAg) and the small t-antigen (tAg). These viral products induce alterations in the normal cell cycle, ultimately leading to cell immortalization and neoplastic transformation . Various authors have detected BKPyV genetic material in a wide range of human tumors . The early BKPyV genome region has been detected in brain tumors, osteosarcomas, Ewing’s tumors, neuroblastomas and genitourinary tract tissues tumors, including prostatic and bladder cancer . In contrast, other authors reported no association between BKPyV DNA and tumors . Here some comparison points for carcinogenicity role of BKPYV: Evidences of BKPyV carcinogenicity:
1- Viral oncogenes are expressed in tumors
2- Tumors developed in in vivo models
3- Transforming properties in vitro models
4- BKPyV alterations occur before immortalization
BKPyV genome detected in human tumors
Evidences for a non-carcinogenic role:
1- Poor and not efficient transforming activity in human cells
2- Ubiquitous distribution in normal human cells and tissues
3- Variable BKPyV presence in tumors among different studies
In conclusion, it is required now is to advise for more epidemiological and experimental studies . In addition, the possibility of interaction with other host-related factors, infectious agents or environmental components for carcinogenesis warrants more investigation
This article is level evidence 5
BK virus belong to DNA virus group Risk factors and pathogenesis: The risk factors include · Factors related to recipient includes: high immunological risk like (HLA incompatibility, ABO incompatibility, and use of antilymphocyte antibodies) which reflect on degree of immunosuppression, diabetes mellitus, rejection episodes, older age, steroid use cytomegalovirus co-infection. · Factors related donor: seropositive renal donor, viruria in the donor.
Level of evidence 5 -Human polyoma viruses are small double stranded DNA viruses with 4 being linked to oncogenicity Merkel cell polyoma virus, SV40, BK virus and JC virus. – BKV has been isolated from: -Urogenital malignancies -brain tumors -osteosarcomas -Ewings tumors But presence of BKV DNA doesn’t essentially possess a neoplastic involvement of the virus. -More studies are needed to show evidence of oncogenesis by BKV infection.
This article is surrounding the role of BK virus in cancer. BK virus is a small DNA virus that belongs to the polyomavirdiae family. It is possible that this virus has an etiological link with cancer. In particular, Merkel cell polyomavirus is linked with a skin cancer called Merkel cell carcinoma.
This article looks at BKV in a wholesome manner, from, biology, entry, epidemiology to mechanisms involved in human carcinogenesis.
Discussion
BKV infection is a primary infection that occurs in early childhood, generally between the ages of 5-9 years. Following primary infection, BKV remains in the kidneys, and causes significant morbidity especially in immunocompromised patients. Complications in the immunocompromised population may include hemorrhagic cystitis and nephropathy.
Transmission can occur through the feco-oral route. Vertical transmission can also occur from mother to fetus.
Viral products of BKV genome induce alterations normal cell cycle of the host, leading to cell immortalization and neoplastic transformation. Transforming ability of BKV depends on its two oncoprotiens – large T antigen (TAg) and small T antigen (tAg). TAg, the larger protein, is highly multifunctional and can bind to several cellular proteins, changing signaling pathways that are involved in cell control. p53 and pRb tumor suppressor proteins are some important proteins that are bound by TAg. This interaction leads to DNA damage and unscheduled onset of S phase.
Conclusion
Further studies are needed to understand the etiology of BKV in cancer and also to mitigate treatment strategies that would prevent or restore DNA damage caused by BKV. In order to achieve this, more environmental and epidemiological studies are necessary.
Another aspect to investigate regarding this topic would be interaction of the virus with host associated factors, infectious agents, and environmental components.
Level of evidence
This is a narrative review, thus level of evidence is 5.
Introduction:
Human polyomaviruses (HPyV) belong to the polyomaviridae family and are small, icosahedral DNA viruses. The HPyV genome, consisting of approximately 5000 base pairs, encodes three regions: the early coding region (large T and small t antigen), non-coding region, and late coding region (involved in gene regulation). Among the polyomaviruses, SV40, BKPyV, JCPyV, and MCPyV have been implicated in oncogenic potential, particularly in rare skin cancer and Merkel cell carcinoma.
Epidemiology:
Primary infections with HPyV commonly occur in early childhood, with a seroprevalence ranging from 65% to 90% in children aged 5 to 9 years. Transmission of the virus can occur through fecal-oral route, vertical transmission, or transplacental transmission. Currently, there is no conclusive evidence establishing a causal relationship between BKPyV and cancer in humans, as the presence of BKPyV in the body may not necessarily indicate its involvement in the neoplastic process.
Role in Carcinogenesis:
The large T antigen and small t antigen encoded by BKPyV have been associated with cellular alterations and neoplastic transformation. Animals injected with BKPyV have developed various tumors such as ependymomas, pancreatic islet cell tumors, osteosarcomas, and others. The process of carcinogenesis may involve mutations, integration of viral sequences into the host genome, inactivation of tumor suppressor proteins, chromosomal alterations and instability, and potential co-factors in carcinogenesis. BKPyV has also been associated with bladder and prostate cancer, but the exact mechanisms remain unclear. The “hit-and-run” carcinogenesis mechanism has been proposed, where the virus may play a role in initiating the process but is not directly involved in the development of cancer.
Conclusion:
Currently, there is no conclusive evidence establishing a causal relationship between BKPyV and cancer in humans. Therefore, further epidemiological and experimental studies are urgently needed to elucidate this relationship and provide more concrete evidence.
Level of Evidence:
The level of evidence provided by this article is Level V.
The aim of this study was to investigate the molecular mechanisms underlying human polyomaviruses (BKPyV) infection and its potential association with malignancy.
Introduction:
Human polyomaviruses (HPyVs) belong to the polyomaviridae family and are small, non-enveloped, double-stranded DNA viruses. The HPyV genome encodes early antigens, small-t/large-T antigens, and late structural proteins such as VP1, VP2, VP3, and agnoprotein. HPyVs can establish a productive infection in their natural hosts, while in non-permissive hosts, they can establish latency and potentially integrate into the host genome. Among the 14 described HPyVs, four polyomaviruses (SV40, BKPyV, JCPyV, and MCPyV) have shown oncogenic potential, with MCPyV being strongly associated with cancer. The potential carcinogenic role of SV40 remains controversial.
Role in Carcinogenesis:
The oncogenic properties of BKPyV have been demonstrated in vitro and in vivo experimental models. BKPyV encodes two viral oncoproteins, large T-antigen and small t-antigen, which can induce alterations in the normal cell cycle and result in neoplastic transformation. BKPyV large T-antigen interacts with cellular proteins, affecting signaling pathways involved in cell cycle control. Animals injected with BKPyV frequently develop various types of tumors. However, while BKPyV’s transforming ability is well-documented in experimental rodent models, definitive evidence of its transforming activity in humans and primates is inconsistent.
Evidence of BKPyV Carcinogenicity:
Several lines of evidence support the potential carcinogenicity of BKPyV, including the expression of viral oncogenes in tumors, tumor development in in vivo models, and the transforming properties observed in in vitro models. Additionally, BKPyV alterations have been detected before immortalization, and BKPyV genomes have been found in human tumors.
Evidence for a Non-Carcinogenic Role:
On the other hand, there is evidence suggesting a non-carcinogenic role for BKPyV. Its transforming activity in human cells is less efficient compared to experimental models, and the virus is ubiquitously distributed in normal human cells and tissues. The presence of BKPyV in tumors varies among different studies.
Conclusion:
Conclusive evidence is necessary to confirm or exclude the role of BKPyV in tumor development. Further epidemiological and experimental studies are required to shed more light on this topic. The possibility of interactions between BKPyV and other host-related factors, infectious agents, or environmental components in carcinogenesis warrants further investigation.
Level of Evidence:
The level of evidence provided by this article is Level V.
Abstract:
DNA viruses classified into the Polyomaviridae family, are widely distributed in human populations.
Thirteen distinct HPyVs have been described to date. Some of these viruses have been found in human tumors, suggesting an etiological relationship with cancer
. In particular, convincing evidence of an oncogenic role has emerged for a specific HPyV, the Merkel cell polyomavirus (MCPyV). This HPyV has been linked to rare skin cancer, Merkel cell carcinoma (MCC).
In 2012, the International Agency for Research on Cancer (IARC) evaluated the carcinogenicity of the BK virus (BKPyV), reporting that BKPyV is “possibly carcinogenic to humans. Background:
HPyVs are small, nonenveloped, double-stranded DNA viruses.
Polyomaviridae family.
The HPyV genome encodes early small-t/large-T antigens as well as late structural proteins called VP1, VP2, VP3, and agnoprotein.
The early region, is composed of large T and small t antigen genes and the splice variants T = 135, T = 136, and T = 165. HPyV capsid harbors 72 pentamer of VP1, which interacts with the VP2/VP3 molecules associated with each pentamer.
These viruses encode a pre-miRNA for generation of two mature miRNAs, a non-coding control region (NCCR).
A non-coding control region (NCCR) is located between the oppositely-oriented transcriptional units that encode for early and late transcripts. The NCCR contains the promoters and enhancers for regulation of gene expression and harbors the replication origin.
Agnoprotein is expressed from the 5’region of VP2 open reading frame. It is believed that this protein is involved in various functions related to the HPyV life cycle, such as regulating viral gene expression or inducing viral maturation.
Fourteen HPyVs have been described, most of which were discovered in the last few years.
Four polyomaviruses have been found to show oncogenic potential — SV40, BKPyV, JCPyV, and MCPyV — although there is strong evidence of such a link only in the case of MCPyV. This virus appears to play a role in a rare skin cancer, Merkel cell carcinoma. Entry of Virus:
Contact between the terminal sialic acid residue of GD3 and VP1 is essential for virus infection.
BKPyV entry is caveolin- and clathrin-independent.
Enter nucleus via the importin-α/β pathway, guided by nuclear localization signals present in the minor capsid proteins VP2 and VP3. Tropism and epidemiology: The primary infection:
Most often occurs in early childhood, with a Seroprevalence of 65–90% in 5–9 year-old children .Following primary infection, BKPyV persists in the kidneys.
If the host becomes immunosuppressed, the virus causes significant morbid.
BKPyV causes hemorrhagic cystitis and nephropathy (BKAN). Transmission mechanism:
Most likely fecal-oral, Tran’s placental transmission is suggested.
Infection in a permissive host cell, early gene expression leads to DNA replication, followed by late gene expression, production of progeny viral particles and cell death.
A non-permissive cell, BKPyV lytic replication is blocked, and abortive infection may result in oncogenic transformation.
There is no conclusive evidence of a causal relationship between BKPyV and cancer in human beings. Role in carcinogenesis:
The oncogenic properties of BKPyV are well demonstrated in in vitro and in vivo
TAg are the p53 family proteins and pRb tumor suppressor proteins. The interaction between BKPyV TAg and p53 results in the inactivation of this protein, interfering with the response to DNA damage and inducing the unscheduled onset of the S-phase. Addition, the interaction between BKPyV TAg and pRb leads to the release and nuclear translocation of the E2 factor (E2F) family of transcription factors and subsequent expression of genes, inducing quiescent cells to enter the S-phase.
Animal injected with BKPyV frequently developed ependymomas, pancreatic islet tumors, osteosarcomas, fibro sarcomas, liposarcomas, osteosarcomas, nephroblastomas and gliomas. Primary hepatocellular carcinomas and renal tumors.
Although the transforming ability of BKPyV is well documented in experimental rodent models, definitive transforming activity is not always observed in human and primate. Conclusion:
The challenge now is to devise investigative strategies that might lead to conclusive evidence that would allow us to confirm or exclude the role of BKPyV in the development of tumor. Level of evidence V.
Abstract:
Human polyomaviruses are DNA viruses belong to polyomaviridae family,
There are 13 types of virus Some of these viruses have been found in human tumors, suggesting an etiological relationship with cancer.
convincing evidence of an oncogenic role has emerged for a specific HPyV, the Merkel cell polyomavirus (MCPyV).
This HPyV has been linked to rare skin cancer, Merkel cell carcinoma (MCC).
In 2012, (IARC) reporting that BKPyV is “possibly carcinogenic to humans.” Background:
Human polyomavirus is virus. Infection started early in life and become dormant .the infection route is through fecooral root and may also with trans placental transmission .
Four polyomaviruses have been found to be carcinogenic — SV40, BKPyV, JCPyV, and MCPyV — which is linked to Merkel cell carcinoma Tropism and epidemiology:
The primary infection is acquired in early childhood, with a sero-prevalence of 65–90% in 5–9 year old children..
Post primary infection, BKPyV it persists dormant in the kidneys.
In immune-incompetent state , the virus reactivate and cause nephropathy (BKAN) in renal transplant patients.
BKPyV genomes have also been detected in liver, stomach, lungs, parathyroid glands, brain, bladder, uterine cervix and prostate. Role of BKPV in carcinogenesis:
1) Viral oncogenes are expressed in tumors.
2) Tumors developed in in vivo models.
3) Transforming properties in in vitro models
4) BKPyV alterations occur before immortalization
5) BKPyV genome detected in human tumors Conclusion:
The challenge now is to devise investigative strategies that might lead to conclusive evidence that would allow us to confirm or exclude the role of BKPyV in the development of tumors. Thus, more epidemiological and experimental studies are strongly required. Level of evidence is 5
In 2012, the International Agency for Research on Cancer (IARC) evaluated the carcinogenicity of the BK virus (BKPyV), reporting that BKPyV is “possibly carcinogenic to humans.” This review explores the BKPyV infection from a historical point of view, including biological aspects related to viral entry, tropism, epidemiology and mechanisms potentially involved in BKPyV-mediated human carcinogenesis.
Evidences of BKPyV carcinogenicity–
Viral oncogenes are expressed in tumors.
Tumors developed in in vivo models.
Transforming properties in in vitro models
BKPyV alterations occur before immortalization
BKPyV genome detected in human tumors
Evidences for a non-carcinogenic role-
Poor and not efficient transforming activity in human cells.
Ubiquitous distribution in normal human cells and tissues.
Variable BKPyV presence in tumors among different studies
Conclusion- The challenge now is to devise investigative strategies that might lead to conclusive evidence that would allow us to confirm or exclude the role of BKPyV in the development of tumors. Thus, more epidemiological and experimental studies are strongly required
Abstract
Human polyomaviruses (HPyV), are DNA viruses belong to polyomaviridae family, it common .
Thee is 30 types of virus . Some of these viruses have been found in human tumors, suggesting an etiological relationship with cancer.
convincing evidence of an oncogenic role has emerged for a specific HPyV, the Merkel cell polyomavirus (MCPyV).
This HPyV has been linked to rare skin cancer, Merkel cell carcinoma (MCC).
In 2012, (IARC) reporting that BKPyV is “possibly carcinogenic to humans.” Background:
Human polyomaviruses is virus. Infection started early in life and become dormant . the infection route is through feco oral root and may also with trans placental transmission .
Four polyomaviruses have been found to be carcinogenic — SV40, BKPyV, JCPyV, and MCPyV — which is linked to Merkel cell carcinoma
Tropism and epidemiology:
The primary infection is acquired in early childhood, with a sero-prevalence of 65–90% in 5–9 year old children.
Post primary infection, BKPyV it persists dormant in the kidneys.
In immune-incompetent state , the virus reactivate and cause nephropathy (BKAN) in renal transplant patients.
BKPyV genomes have also been detected in liver, stomach, lungs, parathyroid glands, brain, bladder, uterine cervix and prostate .
Permissive cells for viral replication are kidney cells, primary human renal proximal tubule epithelial cells and some salivary glands cells.
In a non-permissive cell, BKPyV replication is blocked, and abortive infection may result in oncogenic transformation.
The oncogenic activity of BKPyV is well documented at vitro but there is no conclusive link to cancer. Role of BKPV in carcinogenesis:
– The transforming activity has been mapped in the early region of the BKPV genome, which encodes two viral oncoproteins: Tag and tAg.
– BKPV is highly oncogenic in rodents.
– Conclusive transforming activity of virus is not always conclusive.
– BKPV genetic material is found in wide range of human tumors: brain tumors, osteosarcomas, Ewing’s tumors, neuroblastomas, prostatic, & bladder cancer. But this is not approve for a causative link.
– BKPV may present as co-infection in cells infected by another oncogenic virus (HTLV-I, HCV, HPV, EBV, HHV-8 & HBV).
– Monini et al. found BKPV in about 60% of healthy prostates and prostatic cancer. .
Conclusion
– The challenge now is to devise investigative strategies that might lead to conclusive evidence that would allow us to confirm or exclude the role of BKPyV in the development of tumors.
– Thus, more epidemiological and experimental studies are strongly required.
– the possibility of interaction with other host-related factors, infectious agents or environmental components for carcinogenesis warrants more investigation.
Human polyomaviruses (HPyVs) are small, nonenveloped, double-stranded DNA viruses belong to the polyomaviridae family.
-The HPyV genome encodes early coding region, late coding region and non-coding control region NCCR.
-Around 14 HPyVs discovered. Four viruses have been found to show oncogenic potential — SV40, BKPyV, JCPyV, and MCPyV.
-Skin cancer and Merkel cell carcinoma are strong linked to MCPyV.
Viral entry virus gains entry into the cell thereafter it reaches to the nucleus for replication, once in the endoplasmic reticulum, partial disassembly occurs and the viral particles escape to the cytoplasm finally entering the nucleus
Tropism & epidemiology
Strict anthroponosis BKPyV is widespread. The seroprevalence is 65–90% in 5–9-year-olds, indicating early infection. Kidneys harbor BKPyV after initial infection. When immunosuppressed, the virus causes considerable morbidity. In bone marrow and kidney transplant patients, BKPyV induces hemorrhagic cystitis and BKAN.
The transmission route is unknown, although BKPyV’s great resistance to environmental inactivation and large quantities in human sewage and other water sources imply fecal-oral transmission. Since salivary glands and oropharyngeal cells do not survive BKPyV, the digestive system may be critical for viral transmission.
Role in carcinigenesis
The oncogenic properties of BKPyV are welldemonstrated in in vitro and in vivo
Two viral oncoproteins: the large T-antigen (TAg) and the small t-antigen (tAg)
The interaction between BKPyV TAg and p53 results in the inactivation of this protein, interfering with the response to DNA damage and inducing the unscheduled onset of the S-phase
Transforming ability of BKPyV is welldocumented in experimental rodent models, definitive transforming activity is not always observed in human
Inactivation of tumour suppressor gene has a role .
Alteration in chromosomal activity
Main association with bladder and prostate cancer.
Conclusion Need conclusive evidence to confirm the association and exclusion of BKVPyL with carcinomas. Interaction of infectious agents and environmental components in carcinogenesis.
What is the level of evidence provided by this article?
– Human polyomaviruses (HPyV) are small DNA viruses belonging to the polyomaviridae family
– 13 distinct HPyVs have been described so far, with some being found in tumors
– HPyV infection occurs early in life through fecal-oral transmission
– 4 polyomaviruses have been found to have oncogenic potential i.e., SV40, BKPyV, JCPyV and MCPyV
– strong evidence only exists for MCPyV which is associated with merkel cell carcinoma, a rare skin cancer
BK virus viral entry
– virus gains entry into the cell thereafter it reaches to the nucleus for replication, once in the endoplasmic reticulum, partial disassembly occurs and the viral particles escape to the cytoplasm finally entering the nucleus
Tropism and epidemiology
– primary infection occurs in childhood, the virus persists in the kidneys
– in cases of immunosuppression, there is reactivation resulting in
hemorrhagic cystitis and BKVAN in bone marrow and kidney transplant recipients respectively
– modes of transmission include fecal-oral, vertical/ transplacental transmission
Role in carcinogenesis
– the oncogenic properties of BKPyV have been demonstrated in in vitro and in vivo experimental models
– 2 viral oncoproteins have been described i.e., large T-antigen (TAg) and small t-antigen (tAg)
– these viral products cause alterations in the normal cell cycle eventually leading to cell immortalization and neoplastic transformation
– Merkel cell polyomavirus has an oncogenic role in merkel cell carcinoma (MCC) which is a rare skin cancer
– BKPyV genetic material has been detected in various cancers like prostate, bladder, renal, brain, osteosarcomas
– there are some arguments for BKPyV carcinogenicity and these include: –
Viral oncogenes being expressed in tumors
Tumors being developed in vivo models
Transforming properties in in vitro models
BKPyV genome being detected in human tumors
BKPyV alterations occurring before immortalization
– overall, it has become difficult to demonstrate the carcinogenic role of BKPyV
Conclusion:
– the main challenge is coming uo with strategies that will confirm or exclude the role of BKPyV in carcinogenesis
– more studies are required to answer this question
Level of evidence provided by this article:
Level V
1. Please summarize this article. This is a Review article Introduction · Four of the 14 polyomaviruses (SV40, BKPyV, JCPyV, and MCPyV) have been found to show oncogenic potential. · Some of these viruses have been found in human tumors, suggesting an etiological relationship with cancer. · The International Agency for Research on Cancer (IARC) in 2012 reported BKPyV to be “possibly carcinogenic to humans.” · There is strong evidence of link in the case of MCPyV and Merkel cell carcinoma. A carcinogenic role for SV40 also suspected but the association remains controversial. · This review explores biological aspects of BKPyV, molecular mechanisms in carcinogenesis and its potential association with human cancers. Viral entry · Mainly through respiratory and faeco-oral route. · BKPyV entry inside the cells is caveolin- and clathrin-independent – may be utilizing an as-yet uncharacterized endocytic pathway. · Finally, the virus enters the nucleus via the importin-α/β pathway, guided by nuclear localization signals present in the minor capsid proteins VP2 and VP3. Epidemiology and tropism · Human polyomaviruses (HPyVs) are ubiquitous. · After primary infect in early childhood, and remain latent in kidney and urothelium, with potential integration into the host genome. BKPyV genomes have also been detected in a wide spectrum of normal tissues. · Upon BKPyV infection in a permissive host cell, early gene expression leads to DNA replication, followed by late gene expression, production of progeny viral particles and cell death. In a non-permissive cell, lytic replication is blocked, and abortive infection may result in oncogenic transformation · Although the oncogenic activity of BKPyV is well documented in laboratory settings, there is no conclusive evidence of a causal relationship between BKPyV and cancer in human beings. Role in carcinogenesis: (Lab models)
oncogenic properties of BKPyV are demonstrated in in vitro and in vivo experimental models.
Viral oncoproteins large T-antigen (TAg) and small t-antigen (tAg) are found to induce alterations in the cell cycle, leading to cell immortalization and neoplastic transformation.
TAg interacts with and inactivates p53 à interfere with the response to DNA damage, and induces unscheduled onset of S-phase of cell cycle.
TAg and pRb interaction lead to the release and nuclear translocation of transcription factors (E2F) with subsequent expression of genes which induce quiescent cells to enter the S-phase.
Thus, BKPyV TAg drives the cell to override key cell cycle checkpoint, favoring accumulation of genetic alterations.
BKPyV tAg inactivates mitogen-activated protein kinase (MAPK), leads to activation of signaling pathways that promote cell proliferation.
Early reports demonstrated that BKPyV is highly oncogenic in rodents, but a definitive transforming activity is not always observed in human and primates.
Various authors have detected BKPyV DNA in a wide range of human tumors, while other reports reveal no association – its mere presence may not reflect a direct neoplastic involvement, but could play as co-factor in the carcinogenic process.
The association of BKPyV with HPV16 in high grade CIN suggests that this virus could be involved in HPV16-induced cell transformation. Further experimental studies and clinical observations are needed to verify whether this putative transformation mechanism involving BKPyV and HPV occurs in cervical cancer.
BKV in Renal, bladder and Prostate cancer · Some studies demonstrate BKPyV DNA sequences at high frequencies in bladder carcinoma. However, these studies were small case series that either lacked a control group or relied entirely on antibody seroprevalence. · Although associations between BKPyV and these tumors are rare, the virus may have a tumorigenic role in some cases · possible oncogenic mechanism involves deregulation of the proliferation inducer Tag Conclusion: · Exact role of BK virus in human cancer is not clearly discernible. o more epidemiological and experimental studies are strongly required. · The possibility of interaction with other host-related factors, infectious agents or environmental components for carcinogenesis warrants more investigation. 2. What is the level of evidence provided by this article? Level – 5 (Narrative review)
1. Please summarise this article; BK virus belongs to a family of polyomavirus family, small double-stranded non-enveloped DNA virus, categorized into four groups with different virulence. SV40 has been weak association with malignancy. Viral entry; Its entry is via caveolin and clathrin independent mechanism, when get entrance it proceed to the nucleus for replication via the alpha and beta pathway. Epidemiology and tropism; Remain dormant state in epithelial cells of tubular, parietal, transitional structure, and bowman’s capsules. The incidence of shedding in immunocompetent patient is around 20%, the incidence of shedding of viruria in immunocompromissed recipient is around 60%. In pregnant women the shedding disappear two weeks after delivery. The prevalence of BKVN in renal transplant recipient is 5%, primary infection is in first decade life, possible routes droplets (airborne), fecal oral, urinary oral rout, blood born, during renal transmission, trans-placental. There is no such evidence association BKPyL and malignancy in humans. Role in carcinogenesis; The early region encodes BKVPyL genome encodes two viral oncogenic protein Tag the large and the tAg(p53 family protein) the small, they induce alteration in normal cell cycle and possible neoplastic transformation, second, it inhibit protein phosphatase PP2A an essential tumor suppressor gene in cell death signaling pathway. There is evidence that BKPyV tAg induces chromosomal instability in embryonic fibroblast and tumorigenesis by alteration in deletion, duplication, and translocation. BKVPyL genome early region detected in Ewings tumor, neuroblastoma, and genitourinary tract tumor, prostate and bladder tumors. BKVPyL can have association of carcinoma with other associated infection like HPV16 in high grade cervical cancers. Conclusion; Need conclusive evidence to confirm the association and exclusion of BKVPyL with carcinomas. Interaction of infectious agents and environmental components in carcinogenesis. Level of evidence V
Human polyomaviruses (HPyVs) are small, non-enveloped, double-stranded DNA viruses with approximately 5000-bp genome and icosahedral symmetry.
Viral entry
During BKPyV infection, VP1 interacts with the α2, 8- SA-containing b-series gangliosides (GD1b/GT1b) for cell attachment
A crystal-like complex of VP1 and the ganglioside GD3 is formed, with several points of contact between VP1 and two sialic molecules of a disialic acid ganglioside.
After entering the cell, the virus must reach the nucleus for replication.
This process depends on acidification and maturation of the endosome and involves retrograde transit of endocytic vesicles to the endoplasmic reticulum (ER)
Once in the ER, partial disassembly occurs. Viral particles escape to the cytoplasm, hijacking ER Derlin family proteins
Finally, the virus enters the nucleus via the importin-α/β pathway, guided by nuclear localization signals present in the minor capsid proteins VP2 and VP3
Role in carcinogenesis:
The transforming activity has been mapped in the early region of the BKPyV genome, which encodes two viral oncoproteins: the large T-antigen (TAg) and the small t-antigen (tAg).
These viral products induce alterations in the normal cell cycle, ultimately leading to cell immortalization and neoplastic transformation.
The most frequently-studied cellular targets of TAg are the p53 family proteins and pRb tumor suppressor proteins.
The interaction between BKPyV TAg and p53 results in the inactivation of this protein, interfering with the response to DNA damage and inducing the unscheduled onset of the S-phase.
Therefore, BKPyV TAg drives the cell to override a key cell cycle checkpoint, favoring the accumulation of genetic alterations during each cell replication cycle
An alternative model for the role of BKPyV TAg in oncogenesis involves the first step in which BKPyV TAg binds to or inactivates tumor suppressor proteins, with a second step leading to cellular oncogene activation documented the presence of BKPyV DNA in association with HPV16 in high-grade cervical squamous intraepithelial lesions
The association of BKPyV with precancerous cervical lesions suggests that this virus could be involved in HPV16-induced cell transformation.
BKV and bladder cancer
there are reports that link BKPyV with metastatic bladder carcinoma in immunosuppressed transplant recipient
BKV and Ca Prostate:
BKPyV may be implicated in the inactivation of these tumor suppressor proteins at early stages of tumorigenesis
Conclusion:
Though BKV may be “potentially carcinogenic”, to clarify the role of this virus in human cancer, more epidemiological and basic research is strongly warranted.
● Function of BKPyV gene products
☆ Early coding region :
▪︎Large Tumour Antigen (Tag)
” Cell cycle progression, inhibition of apoptosis, viral replication”
▪︎Truncated Large T antigen (truncTAg)
” Cell cycle progression, viral replication ”
▪︎Minor T Antigen (tAg)
” Cell cycle progression ”
3p-miRNA and 5p-miRNA
” viral persistence ”
☆ Late coding region :
▪︎VP1
” capsid structure (external), viral attachment and entry ”
▪︎VP2
” capsid structure (internal), involved in viral infectivity ”
▪︎VP3
” capsid structure (internal), involved in viral infectivity ”
▪︎Agno protein
” Life cycle (assembly, maturation, release)”
● After entering the cell, the virus must reach nucleus for replication.
● Once partial disassembly occurs. Viral particles escape to the cytoplasm
● Virus enters the nucleus by signals in the
minor capsid proteins VP2 and VP3
Epidemiology
● BKPyV seroprevalence of 65–90% in
5–9 year old children
● BKPyV causes hemorrhagic cystitis and
nephropathy (BKAN) in bone marrow and renal transplant patients, respectively
● Fecal-oral transmission and a vertical transmission only in primary BKV infection
● Salivary glands and oropharyngeal cells are not involved in BKPyV persistence
● Once the virus enters to the body,(PBLs) transport BKPyV to different organs
● Although the oncogenic activity of BKPyV is well documented This relationship is difficult to demonstrate for several reasons:
☆ The viral agent has a high prevalence in the general population
☆ There are a wide range of human tissues in which the virus can be detected
☆ The virus has the ability to remain in a latent state for long periods
Role in carcinogenesis
● The early region encodes two viral oncoproteins: (TAg) and (tAg).
These induce alterations in the normal cell cycle leading to cell immortalization and neoplastic transformation
● tAg inhibits protein phosphatase 2A an essential tumor suppressor in numerous death-signaling pathways.
● Although BKPyV TAg modulate cellular growth it needs additional events for complete transformation. These events could be mutations or alterations of the viral promoter-enhancer elements, leading to increased expression of early genes and a consequent increase in transforming activity
● BKPyV TAg induces chromosomal instability in human embryonic fibroblasts, characterized by gaps, breaks, dicentric and ring chromosomes, deletions, duplications and translocations
● The early BKPyV genome region has been detected in brain tumors, Ewing’s tumors, osteosarcomas, , neuroblastomas and genitourinary tract tissues tumors, including prostatic and bladder cancer
● The virus may co-infect cells that were previously infected by another oncogenic virus, increasing susceptibility to cancer.
● Patients who develop PVAN are at significantly higher risk of developing cancers which are high-grade and invasive.
● possible oncogenic mechanism involves deregulation of the proliferation inducer TAg
● Human oncogenic virus such as BKPyV may be implicated in the inactivation of these tumor suppressor proteins at early stages of tumorigenesis
● A carcinogenic role has also been suspected for SV40
● The cytoplasmic localization of oncogenic protiens suggests a functional inactivation mechanism by sequestration
● The “hit-and-run” carcinogenesis mechanism is a possible tumorigenic mechanism in which the TAg inactivates p53 in the atrophic cells, increasing susceptibility to genetic alterations, including tumor suppressor gene mutations that may result in early prostate cancer progression.
– Human polyomaviruses (HPyV) are small DNA viruses belonging to the polyomaviridae family
– 13 distinct HPyVs have been described so far, with some being found in tumors
– HPyV infection occurs early in life through fecal-oral transmission
– 4 polyomaviruses have been found to have oncogenic potential i.e., SV40, BKPyV, JCPyV and MCPyV
– strong evidence only exists for MCPyV which is associated with merkel cell carcinoma, a rare skin cancer
BK virus viral entry
– virus gains entry into the cell thereafter it reaches to the nucleus for replication, once in the endoplasmic reticulum, partial disassembly occurs and the viral particles escape to the cytoplasm finally entering the nucleus
Tropism and epidemiology
– primary infection occurs in childhood, the virus persists in the kidneys
– in cases of immunosuppression, there is reactivation resulting in
hemorrhagic cystitis and BKVAN in bone marrow and kidney transplant recipients respectively
– modes of transmission include fecal-oral, vertical/ transplacental transmission
Role in carcinogenesis
– the oncogenic properties of BKPyV have been demonstrated in in vitro and in vivo experimental models
– 2 viral oncoproteins have been described i.e., large T-antigen (TAg) and small t-antigen (tAg)
– these viral products cause alterations in the normal cell cycle eventually leading to cell immortalization and neoplastic transformation
– Merkel cell polyomavirus has an oncogenic role in merkel cell carcinoma (MCC) which is a rare skin cancer
– BKPyV genetic material has been detected in various cancers like prostate, bladder, renal, brain, osteosarcomas
– there are some arguments for BKPyV carcinogenicity and these include: –
Viral oncogenes being expressed in tumors
Tumors being developed in vivo models
Transforming properties in in vitro models
BKPyV genome being detected in human tumors
BKPyV alterations occurring before immortalization
– overall, it has become difficult to demonstrate the carcinogenic role of BKPyV
Conclusion
– the main challenge is coming uo with strategies that will confirm or exclude the role of BKPyV in carcinogenesis
– more studies are required to answer this question
-HPV are non enveloped ,double stranded DNA with approx 5000bp genome and an icosahedral shape. It contains an early and a late region.
-HPV are normally latent in the host until immunosuppression occurs then thy flare and cause an infection.
-x4 types exist;SV40,BKPyV,JCPyV and MCPyV. The latter has been linked to merkel cell carcinoma.SV40 too has been weakly linked to malignancy.
BK VIRUS.
VIRAL ENTRY;
–Contact btn GD3 and VP1 is key for infection to occur. Viral entry is via caveolin and clathrin independent mechanism. Once in the cell it proceeds ti the nucleus for replication via the importin alpha/beta pathway.
TROPISM AND EPIDEMIOLOGY;
–Primary infection occurs in early childhood with a prevalence of 65-90% in 5-9 yr olds. It would then persist in the kidneys and be deadly once immunosuppression occurs. It has been associated with BKAN and hemorrhagic cystitis in BMT and KTR.
-Amongst other modes of transmission, vertical transmission has been reported, post infection, the virus disseminates to other organs via peripheral blood leukocytes.
-There is no solid evidence linking BKPyV and malignancy in the human population.
ROLE IN CARCINOGENESIS;
-Carcinogenic property is linked to early region that encodes oncoproteins ;TAg and tAg that alter normal cell cycle leading to neoplastic transformation.
TAg interacts with p53 and pRb tumor suppressor proteins ,altering them and interfering with cell cycle with resultant uncontrolled cell proliferation + chromosomal instability.
-tAg blocks PP2A ,activating signal pathways that promote cell proliferation leading to oncogenesis.
-Animals injected with BKPyV have been found to develop ependymomas, pancreatic islet tumors, osteosarcomas, liposarcomas, nephroblastoma, gliomas, HCC and RCC. This is yet to be documented in humans.
-Some authors have found BKPyV genes in brain tumors, osteosarcomas, erwings tumor, neuroblastoma and GUT tumors-Prostate and bladder.
-BKPyV has also been found in an unclear association with HPV16 in high grade cervical squamous intraepithelial lesions. More studies are needed in this.
-Unlike in immunocompetent, immunocompromised have had an association btn BKPyV to metastatic bladder ca partly due to propensity of the virus to reside in urothelial cells.
-In prostate ca, we have mixed results that are inconclusive on contribution of BKPyV to prostate Ca despite extensive research on the same.
CONCLUSION.
Carcinogenic role of thus virus in humans is not yet established and more studies are definitely needed.
· BKV DNA was found in wide range of tumors as brain tumors, Ewing sarcoma, neuroblastoma and genitourinary tumors as bladder and prostate. However, it is still needing further research to find it is causation or just an association.
· BKV infection was described to increase invasion and aggressiveness of bladder cancer in immunocompromised patients.
· Merkel virus one of polyoma viruses was linked to rare type of skin cancer, Merkel carcinoma.
Summary of the article Role of BK human polyomavirus in cancer
Four polyomaviruses have been found to show oncogenic potential; SV40, BKPyV, JCPyV, and MCPyV.
The transforming activity has been mapped in the early region of the BKPyV genome, which encodes two viral oncoproteins that induce alterations in the normal cell cycle leading to cell immortalization and neoplastic transformation: · the large T-antigen (TAg). · the small t-antigen (tAg). Early BKPyV genome region has been detected ina wide range of human tumors: · Brain tumors. · Osteosarcomas. · Ewing’s tumors. · Neuro- blastomas. · Genito-urinary tract tissues tumors including prostatic and bladder cancer. · High-grade cervical squamous intraepithelial lesions: in association with HPV16. · MCPyV; appears to play a role in a rare skin cancer, Merkel cell carcinoma.
The level of evidence provided by this article
This is a narrative review article with level of evidence grade 5.
This review is done to evaluate the molecular mechanisms of BKPyV infection and its potential association with cancer.
Human polyomaviruses (HPyVs) are small, nonenveloped, double-stranded DNA viruses, belong to the polyomaviridae family. It encdes early small-t/large-T antigens as well as late structural proteins called VP1, VP2, VP3, and agnoprotein.
The HPyV capsid harbors 72 pentamers of VP1, which interacts with the VP2/VP3 molecules associated with each pentamer .
HPyV encode a pre-miRNA for generation of two mature miRNAs . A non-coding control region (NCCR) is located between the oppositely-oriented transcriptional units that encode for early and late transcripts. The NCCR contains the promoters and enhancers for regulation of gene expression and harbors the replication origin (Ori) . In BKPyV, JCPyV, and SV40, the agnoprotein is expressed from the 5’region of VP2 open reading frame. It is believed that this protein is involved in regulating viral gene expression or inducing viral maturation . In immunocompetent people the virus remains latent with potential integration into the host genome. while in immunosuppressed patients it may reactivate and establish a productive infection. HPyV infection typically occurs in childhood , often through fecal-oral transmission, and persists throughout the lifespan. Fourteen HPyVs have been described, most of which were discovered recently . Four polyomaviruses have been found to show oncogenic potential — SV40, BKPyV, JCPyV, and MCPyV . MCPyV appears to play a role in a rare skin cancer, Merkel cell carcinoma . A carcinogenic role has also been suspected for SV40, but the association remains controversial as no robust evidence has emerged. BK virus Viral entry:
A specific contact between the terminal sialic acid residue of GD3 and VP1 is essential for virus infection. After entering the cell viral particles escape to the cytoplasm,, then enters the nucleus guided by nuclear localization signals present in the minor capsid proteins VP2 and VP3 .
Tropism and epidemiology:
The primary infection most often occurs in early years of life , with a seroprevalence of 65–90% in 5–9 year old children .
BKPyV persists in the kidneys following primary infection, and reactivated causing significant morbidity when the host becomes immunosuppressed. BKPyV causes hemorrhagic cystitis in bone marrow transplant and nephropathy (BKAN) in renal transplant patients . viral transmission is mainly through fecal-oral route . Another mode of transmission is a vertical transmission of this and transplacental transmission . Once the virus enters the body, probably peripheral blood leukocytes (PBLs) transport BKPyV to different sites and organs . Upon BKPyV infection in a permissive host cell, early gene expression leads to DNA replication, followed by late gene expression, production of progeny viral particles and cell death. Permissive cells include human embryonic kidney cells or primary human renal proximal tubule epithelial cells and some salivary glands cells .
In a non-permissive cell, BKPyV lytic replication is blocked, and abortive infection may result in oncogenic transformation but there is no conclusive evidence of a causal relationship between BKPyV and cancer in human beings.
Role in carcinogenesis :
The oncogenic properties of BKPyV are well demonstrated in in vitro and in vivo experimental models. The early region of the BKPyV genome encodes two viral oncoproteins: the large T-antigen (TAg) and the small t-antigen (tAg). These viral products induce alterations in the normal cell cycle, leading to neoplastic transformation .
The most frequently-studied cellular targets of TAg are the p53 family proteins and pRb tumor suppressor proteins. The interaction between BKPyV TAg and p53 results in the inactivation of this protein, interfering with the response to DNA damage and inducing the unscheduled onset of the S-phase .
Therefore, BKPyV TAg drives the cell to override a key cell cycle checkpoint, favoring the accumulation of genetic alterations during each cell replication cycle .In addition, the interaction between BKPyV TAg and pRb leads to the release and nuclear translocation of the E2 factor (E2F) family of transcription factors and subsequent expression of genes, inducing quiescent cells to enter the S-phase.
Another early gene product of BKPyV, the small tAg, plays an important role in transformation by inhibiting protein phosphatase 2A (PP2A), an essential tumor suppressor in numerous death-signaling pathways.
Early reports demonstrated that BKPyV is highly oncogenic in rodents . In addition, animals injected with BKPyV frequently developed ependymomas, pancreatic islet tumors, osteosarcomas, fibrosarcomas, liposarcomas, osteosarcomas, nephroblastomas and gliomas .
BKPyV TAg may modulate cellular growth through direct interactions with critical regulatory proteins but additional events are required for complete transformation. These events could be mutations or alterations of the viral promoter enhancer elements, leading to increased expression of early genes and a consequent increase in transforming activity Moreover, it has been shown that BKPyV TAg induces chromosomal instability in human embryonic fibroblasts, characterized by gaps, breaks, dicentric and ring chromosomes, deletions, duplications and translocations Consistent with early participation of BKPyV TAg in tumorigenesis, there is evidence that these alterations occur before immortalization . Various authors have detected BKPyV genetic material in a wide range of human tumors . For instance, the early BKPyV genome region has been detected in brain tumors, osteosarcomas, Ewing’s tumors, neuroblastomas and genitourinary tract tissues tumors, including prostatic and bladder cancer .
In some cases, BKPyV may not be directly involved in the development of cancer, but instead, play a role as a co-factor in the carcinogenic process. The virus may co-infect cells that were previously infected by another oncogenic virus, increasing susceptibility to malignancy .
Recent reports have documented the presence of BKPyV DNA in association with HPV16 in high-grade cervical squamous intraepithelial lesions but further experimental studies are needed .
Renal cancer, urothelial bladder cancer, and prostatic cancer have been extensively studied because BKPyV has a tropism for certain cell types and remains latent or persistent in the kidney and urinary tract .Therefore, carcinomas that affect this anatomical zone are likely candidates for associations with BKPyV. The contribution of BKPyV to the etiology of bladder carcinoma in immunocompetent individuals is not well established .
Recent findings using deep sequencing analysis from a high-grade BKPyV-associated tumor expressing TAg have revealed viral DNA integrated into the host genome that lead to blockage of viral replication and suggests a concomitant disruption of regulatory feedback signals that control TAg expression. Prostate cancer( PCa ) is one of the leading causes of cancer deaths in men worldwide, and its relationship with BKPyV infection has been studied by several groups in recent years In this context, it has been postulated that BKPyV constitutes an important factor for early prostate tumorigenesis . In conclusion : More epidemiological and experimental studies are strongly required. In addition, the possibility of interaction with other host-related factors, infectious agents or environmental components for carcinogenesis warrants more investigation.
What is the level of evidence provided by this article?
Please summarise this article. Background
Human polyomaviruses (HPyVs) are small, nonenveloped,
double-stranded DNA viruses .These viruses belong to the polyomaviridae family.
– HPyV infection typically occurs early in life, often through fecal-oral transmission, and persists throughout the lifespan .
– Fourteen HPyVs have been described, most of which were discovered in the last few years .
-Four polyomaviruses have been found to show oncogenic potential — SV40, BKPyV, JCPyV, and MCPyV — although there is strong evidence of such a link only in the case of MCPyV. This virus appears to play a role in a rare skin cancer, Merkel cell carcinoma. BK virus Tropism and epidemiology
-The primary infection most often occurs in early childhood, with a seroprevalence of 65–90% in 5–9 year old children . Following primary infection, BKPyV persists in the kidneys. If the host becomes immunosuppressed, the virus causes significant morbidity.
-BKPyV causes hemorrhagic cystitis and nephropathy (BKAN) in bone marrow and renal transplant patients, respectively .
-Transmission mechanisms fecal-oral transmission and vertical transmission .
-There is no conclusive evidence of a causal relationship between BKPyV and cancer in human beings. Role in carcinogenesis
-The oncogenic properties of BKPyV are welldemonstrated
in in vitro and in vivo experimental models.
-The early BKPyV genome region has been detected in brain tumors, osteosarcomas, Ewing’s tumors, neuroblastomas and genitourinary tract tissues tumors, including prostatic and bladder cancer .
– BKPyV may co-infect cells that were previously infected by another
oncogenic virus, increasing susceptibility to cancer. In fact, HPyVs have been detected in various tissues that are susceptible to transformation by HTLV-I, HCV, HPV, EBV, HHV-8 and HBV.
– Recent reports have documented the presence of BKPyV DNA in
association with HPV16 in high-grade cervical squamous intraepithelial lesions.
-studies showed that patients who develop PVAN are at significantly
higher risk of developing cancers, including transitional cell bladder carcinoma .
-Urothelial carcinomas expressing BK TAg are quite rare, these cancers show some distinct features. These tumors are high-grade and invasive. Lesions can arise in the renal allograft or the host urothelial tissue.
-Monini et al. detected BKPyV in approximately 60% of cancerous and healthy prostates, and the viral load was found to be significantly higher in neoplastic as compared to non-neoplastic tissue .
-These apparently contradictory data can be partially explained due to the variable sensitivity and specificity of the detection methods used
in each study.
– it has been postulated that BKPyV constitutes an important factor for early prostate tumorigenesis .
What is the level of evidence provided by this article?
Level 5
BK polyoma virus BKPyv: infection is one the most important causes of morbidity and mortality post transplantation with specific impact on allograft function and progression of kidney disease.
Polyoma viruses are extremely common , attracted early in life mainly via fecal oral rout, and has reported prevalence of 60-90% by age of 5-9 years. After primary infection:
BKPyv dwell in the kidney and persevere for years . When the host turned to be immunodeficient, particularly , after kidney transplantation, the virus emerge to replicate and inflict renal diseases in the form of hemorrhagic cystitis and nephropathy reported in the context of bone marrow transplantation and kidney transplantation respectively. Rout of BKPyv infection:
Rout of transmission is usually fecal -oral. After entering to the body ,peripheral blood Leukocytes transport the virus to different organs and tissues. Infection of permissive cells:
When infection permissive cells infected, early gene experssion , leads to DNA replication. with consequent late gene expression, production of progeny viral particles and cell death. Permissive cells for viral infection, are salivary glands cells , renal proximal epithelial cells. Non infection permissive cells:
In those cells BKPyv replication is blocked , abortive infection might results in oncogenic transformation.However, There is no definite relation between BKPyv infection and malignancy.
The relationship is difficult to ascertain due to several factors:
1] BKPyv is extremely prevalent in population.
2 ] BKPyv is widely spead in different human tissues.
3 ]BKPyv is inherently latent for longer duration with occasional activation.
Nevertheless, There were an irrefutable experimental evidences of the oncogenesity of BKPyv, attributable to its two oncoproteins larg T protein[TAg] and small t protein[tAg], which are inflicting alteration in cell cycle resultant in neoplastic transformation. Merkel Cell Polyoma virus MCPyV:
The only exception is MCPyV which is evidently linked to rare skin cancer Merkel cell carcinoma.
This is a review with level evidence of 5.
14 types of polyomavirus have been discovered until recently. Some of which were reported to have an association with malignancy. Relation to cancer became an interest because o the wide spread of this family. Oncogenicity was mostly related in HPyV, MCPyV, HPyV.
BK virus infection starts in childhood. Seroprevalence up to 65-90% before the age of 10. Post-infection it stays in the kidney. But BK was also documented in plenty of tissues like the liver, lymph nodes, brain, saliva etc. The faecal-oral route is the most believed way of infection.
Trasnformin (oncogenic) activity of BK was reported in experimental studies. The large T-antigen (TAg) and small t- antigen (t-Ag) were shown to cause alterations in the cell cycle, but the causality needs to be checked and controlled by more robust controlled studies.
Table 2 in the paper shows details about evidence with/against the carcinogenic role.
Introduction:
Human polyoma viruses are small non-enveloped double stranded DNA viruses that have an icosahedral shape. These viruses are ubiquitous and belong to the polyoma viridae family. The genome consists of approximately 5000 base pairs. The human polyoma virus codes for:
Early Small-t/large-T antigens as well as late structural proteins called VP1, VP2, VP3 and agno-proteins. The early region, which is transcribed before the DNA replication begins, is composed of large T and small t antigen genes and the splice variants T=135, T=136 and T=165. The late region is transcribed concomitant with DNA replication. The human polyoma virus capsid harbors 72 pentamers of VP1 which interact with VP2/VP3 molecules associated with each pentamer. In addition, these viruses encode a pre-miRNA for generation of 2 mature miRNAs.
In natural hosts, human polyoma viruses establish a productive infection, while in heterologous, non-permissive hosts, the virus establishes latency with potential integration into the host genome. Human polyoma virus infection occurs early in childhood, mainly through the feco-oral route. Four polyoma viruses have been found to show oncogenic potential:
SV40
BK virus
JC virus
Merkel cell polyoma virus
The only strong evidence is only found in the case of merkel cell polyoma virus
BK Virus:
Using siRNA strategy, it was demonstrated that the virus entry caveolin- and clathrin independent. These findings together with the fact that the virus entry does not require actin polymerization, excludes other endocytic pathways and suggests that BKV utilizes an as-yet uncharacterized endocytic pathway.
Once in the ER, partial disassembly occurs. Viral particles escape to the cytoplasm, hijacking ER Derlin family proteins. Finally, the virus enters the nucleus via the importing-alpha/beta pathway, guided by nuclear localization signals present in the minor capsid proteins VP2 and VP3
Tropism and epidemiology:
BK virus infection mostly occurs in childhood, with a seroprevalence of 65-90% in 5-9 year old children. Following primary infection, the virus persists in the kidneys. When the host becomes immunosuppressed, the virus causes significant morbidity. It can cause hemorrhagic cystitis and BKVN in HSCT and renal transplant patients respectively.
Once the virus enters in the body, probably peripheral blood leucocytes (PBLs) transport it to the different sites and organs.
Although the oncogenic activity of BKV is well documented in laboratory settings, there is no conclusive evidence of a causal relationship between BKV and cancer in humans. This relationship is difficult to demonstrate in ecological contexts due to several reasons:
The virus has a high prevalence in the general population
There is a wide range of human tissues in which the virus can be detected
The virus can remain latent for long periods with occasional reactivations
Role In Carcinogenesis:
The oncogenic properties of the BK virus are well demonstrated in in vitro and in vivo experimental models. The transforming activity has been mapped in the early region of the BKV genome which encodes two viral oncoproteins: the large T antigen and the small t antigen. These viral products induce alterations in the normal cell cycle, ultimately leading to cell immortalization and neoplastic transformation.BKV large TAg is a highly multifunctional protein that can bind various cellular proteins, altering signaling pathways involved cell cycle control. The most frequently studied cellular targets of TAg are the p53 family proteins and the pRb tumor suppressor proteins. The interaction between BKV TAg and p53 results in inactivation of this protein, interfering with the response to DNA damage and inducing the unscheduled onset of the S-phase. The interaction between BKV TAg and pRb leads to the release and nuclear translocation of the E2 factor family of transcription factors and subsequent expression of genes, inducing quiescent cells to enter the S phase.
Although the transforming ability of the BKV is well documented in experimental rodent models, definitive transforming activity is not always observed in humans and primates.
Various authors have detected BKV genetic material in a wide range of tumors including brain tumors, osteosarcomas , Ewings tumors, neuroblastoma and genitourinary tract tissue tumors including prostate and bladder cancer. In contrast, other authors have not reported an association between BKV DNA and tumors
in any case, the mere presence of BKV DNA does not necessarily reflect a neoplastic involvement of the virus.
There are reports that link BKV to metastatic bladder cancer in transplant recipients. In a retrospective study, Roberts et al reported that while no positive BKV TAg urothelial carcinomas were found in a series of of non-trasnplanted patients, strong nuclear staining for TAg was seen in the urothelial carcinoma of one transplanted patient. This data indicates that although associations between BKV and these tumors are rare, the virus may have a tumorigenic role in some cases.
Prostate cancer is one of the leading causes of cancer deaths in men worldwide, and its relationship with BKV infection has been studied by several groups in recent years. Monin et al detected BKV in approximately 60% of cancerous and healthy prostates, and the viral load was found to be significantly higher in neoplastic as compared to non-neoplastic tissue. Lau et al, using in situ, detected BKV in only 2/30 prostate adenocarcinomas and no TAg expression was detected in neoplastic tissue.
Conclusion:
BKV is a polyoma virus that has a high prevalence in the young and has a tropism for the renal tubular cells and urothelium. There have been in vitro studies showing the association between BKV and tumorigenesis. It has been difficult to establish a causality between BKV and tumors as majority of patients have already been infected by the virus. More robust studies need to be done to establish a relationship between BKV and cancers
Level of evidence: Systematic review – level of evidence V
Summary Background
Human polymaviruses are small non-enveloped double stranded DNA with icosahedral symmetry that belong to the polyomaviridae family.
HPyV infection occur early in childhood with the fecal oral route of transmission and tend to last one”s lifespan.
Currently 14 HPyV have been identified with 4 associated with malignancies, however only MCPyV has strong oncogenic link evidence. MCPyV is associated with Merkel cell carcinoma which is a rare skin cancer.
Tropism and epidemiology.
BKPyV primary infection occurs in early childhood with seroprevalence rates of 65-90% in 5-9 year olds. After primary infection it remains latent in the kidneys. When the host immunity is compromised it causes hemorrhagic cystitis and BKVAN in both bone marrow and renal transplant recipients respectively.
BKPyV infection in a permissive cell leads to gene expression and DNA replication, while infection in a non-permissive cell leads to oncogenic transformation.
Though BKPyV oncogenic properties have been demonstrated in laboratory studies there has been no conclusive evidence of causal relationship in human beings. This is due to the fact that BKPyV has a high prevalence in general population, it can be detected in various tissue and its ability to remain latent for a long period of time.
Role in carcinogenesis
The transforming properties have been mapped out in the early region of the BKPyV genome which codes for viral oncoprotein large T antigen and small t antigen.
This viral proteins induce changes in the normal cell cycle leading to cell immortalisation and neoplastic transformation.
The BKPyV T antigen is a multifunctional protein that can bind various cellular proteins thus altering signalling pathways that are involved in cell cycle control. Most studied is its interaction with p53 and pRb tumour suppressor proteins.
Interaction with p53 leads to its inactivation and induces the cell to unscheduled S-phase.
Interaction with pRb leads to release and nuclear translocation of E2 factor inducing cells to enter S phase.
BKPyV small t antigen inhibits protein phospholipase A2 which is a tumour suppressor.
Although transforming ability of BKPyV has been demonstrated in rodents, definitive transformation lacks in humans and primates.
Studies have shown conflicting results with some reporting an association of BKPyV and tumours and others showing no association.
However the mere presence of BKPyV DNA doesn’t not necessary indicate a neoplastic involvement. In other instances BKPyV may not be playing a direct role but rather a co-factor in the carcinogenic process
Conclusion
Further studies are required to confirm or exclude the role of BKPyV in the development of tumours.
Introduction ; ————————————
Human polyomaviruses (HPyV), which are small DNA viruses classified into the polyomaviridae family, are widely distributed in human populations. Thirteen distinct HPyVs have been described to date. Some of these viruses have been found in human tumors, suggesting an etiological relationship with cancer.
Early findings established that BKPyV has a tropism for certain cell types and that this agent can establish a persistent or latent infection in the kidney and urinary tract .Therefore, carcinomas that affect this anatomical zone are likely candidates for associations with BKPyV.
The viral oncoproteins: —————————————————-
1-The large T-antigen (TAg)
2-The small t-antigen (tAg).
These viral products induce alterations in the normal cell cycle, ultimately leading to cell immortalization and neoplastic transformation .
BKPyV large Tag;
——————————–
Is a highly multifunctional protein that can bind various cellular proteins, altering signaling pathways involved in cell cycle control. The most frequently-studied cellular targets of TAg are the p53 family proteins and pRb tumor suppressor proteins.
The small tAg; ——————————
Plays an important role in transformation by inhibiting protein phosphatase 2A (PP2A), an essential tumor suppressor in numerous death-signaling pathways.
The oncogenic activity of BKPyV;
—————————————————
Although the oncogenic activity of BKPyV is well- documented in laboratory settings, there is no conclusive evidence of a causal relationship between BKPyV and cancer in human beings. This relationship is difficult to demonstrate in ecological contexts for several reasons:
1-The viral agent has a high prevalence in the general population.
2-there are a wide range of human tissues in which the virus can be detected .
3- The virus has the ability to remain in a latent state for long periods, with occasional reactivations.
Evidences of BKPyV carcinogenicity ————————————————————–
1- Viral oncogenes are expressed in tumors.
2- Tumors developed in in vivo model.
3- Transforming properties in in vitro models.
4- BKPyV alterations occur before immortalization .
5- BKPyV genome detected in human tumors .
Evidences for a non-carcinogenic role ; ———————————————————– 1- Poor and not efficient transforming activity in human cells. 2- Ubiquitous distribution in normal human cells and tissues. 3- Variable BKPyV presence in tumors among different studies.
Conclusion; ————————-
Thus, more epidemiological and experimental studies are strongly required. In addition, the possibility of interaction with other host-related factors, infectious agents or environmental components for carcinogenesis warrants more investigation.
What is the level of evidence provided by this article? Level V
# The aim of the study:
*To determine the molecular mechanisms of human polyomaviruses (BKPyV) infection and its relation with malignancy .
# Introduction:
* (HPyVs) are small, non enveloped, dsDNA viruses, it is belong to the polyomaviridae family.
*The HPyV genome encodes early small-t/large-T antigens as well as late structural proteins called VP1, VP2, VP3, and agnoprotein.
*In natural hosts, HPyVs establish a productive infection, while in heterologous, non-permissive hosts, the virus establishes latency with potential integration into the host genome.
*14 HPyVs have been described and 4 polyomaviruses showed oncogenic potential SV40, BKPyV, JCPyV, and MCPyV (MCPyV with strong cancer relation).
* A carcinogenic role has also been suspected for SV40, but the association remains controversial.
# Tropism and epidemiology:
*The primary infection commonly occurs during early childhood, with a seroprevalence of 65–90% in 5–9 year old.
*After primary infection, BKPyV persists in the kidneys, and when the host becomes immunosuppressed, it lead to morbidity.
*It results in hemorrhagic cystitis in BMT and (BKAN) in renal transplantation.
*BKPyV genomes can be found in normal tissues.
*The transmission via fecal-oral route, vertical and transplacental transmission
*In spite of oncogenic effect of BKPyV that had been detected in laboratory context, there is no clear evidence of a causal relationship between BKPyV and malignancies in human beings.
# Role in carcinogenesis:
*The oncogenic properties of BKPyV are well demonstrated in vitro and in vivo experimental models.
* The BKPyV genome, encodes two viral oncoproteins:
Large,T-antigen
Small t-antigen can induce alterations in the normal cell cycle, result in neoplastic transformation.
*BKPyV large TAg is a highly multifunctional protein
that can bind various cellular proteins, altering signaling
pathways involved in cell cycle control.
*Animals injected with BKPyV frequently developed different types of tumors.
*Although the transforming ability of BKPyV is well documented in experimental rodent models, definitive
transforming activity is not always observed in human
and primates
*BKPyV TAg induces chromosomal instability in human embryonic fibroblasts, characterized by gaps, breaks, dicentric and ring chromosomes, deletions, duplications and translocations.
# Evidences of BKPyV carcinogenicity:
*Viral oncogenes are expressed in tumors.
*Tumors developed in in vivo models.
* Transforming properties in in vitro models.
*BKPyV alterations occur before immortalization
*BKPyV genome detected in human tumor.
# Evidences for a non-carcinogenic role:
*Poor and not efficient transforming activity in human cells.
*Ubiquitous distribution in normal human cells and tissues.
*Variable BKPyV presence in tumors among different studies.
# Conclusion
*Conclusive evidence is required to allow confirmation or exclude the role of BKPyV in the development of tumors. *More epidemiological and experimental studies are strongly required.
*The possibility of interaction with other host-related factors, infectious agents or environmental components for carcinogenesis warrants more investigation.
# What is the level of evidence provided by this article?
Human polyomaviruses (HPyVs) are small, non-enveloped, double-stranded DNA viruses.
These viruses belong to the polyomaviridae family.
In natural hosts, HPyVs establish a productive infection, while in heterologous, non-permissive hosts, the virus establishes latency with potential integration into the host genome.
HPyV infection typically occurs early in life, often through fecal-oral transmission, and persists throughout the lifespan.
Four polyomaviruses have been found to show oncogenic potential.
This virus appears to play a role in a rare skin cancer, Merkel cell carcinoma.
BK virus
Viral entry
For cell attachment during BKPyV infection, VP1 interacts with the b-series gangliosides (GD1b/GT1b) that contain 2, 8-SA.
With many sites of interaction between VP1 and two sialic molecules of a di-sialic acid ganglioside, GD3, a complex resembling a crystal is created.
By use of site-directed mutagenesis, this model was investigated.
It was determined that a particular interaction between VP1 and the terminal sialic acid residue of GD3 is necessary for viral infection.
Tropism and epidemiology
BKPyV infection is a widely-distributed strict anthroponosis.
With a seroprevalence of 65–90% in children aged 5–9, the initial infection most frequently affects infants and young children.
BKPyV remains in the kidneys after the initial infection.
A large amount of morbidity is caused by the virus if the host develops immunosuppression.
For instance, BKPyV affects individuals with renal and bone marrow transplants in different ways, leading to hemorrhagic cystitis and nephropathy (BKAN).
BKPyV genomes have also been detected in a wide spectrum of normal tissues including the liver, stomach, lungs, parathyroid glands, lymph nodes, brain, peripheral blood mononuclear cells, bladder, uterine cervix, vulva, prostate, lips, and tongue.
BKPyV is highly resistant to environmental inactivation, suggesting fecal-oral transmission.
Early gene expression leads to DNA replication, production of progeny viral particles, and cell death.
BKPyV lytic replication is blocked, leading to oncogenic transformation.
Role in carcinogenesis
Experimental models both in vitro and in vivo have successfully proven the oncogenic potential of BKPyV.
The early section of the BKPyV genome, which codes for the big T-antigen (TAg) and the tiny t-antigen viral oncoproteins, has been identified as the site of the transforming activity (tAg).
The normal cell cycle is altered by these viral byproducts, which ultimately result in cell immortalization and neoplastic transformation.
Transfection of embryonic fibroblasts with BKPyV DNA leads to cell transformation.
A very versatile protein called BKPyV big TAg may connect to different cellular proteins and change signaling pathways involved in cell cycle regulation.
Additionally, the interaction between BKPyV TAg and pRb causes the nuclear translocation and release of the E2 factor (E2F) family of transcription factors, which in turn causes gene expression and induces quiescent cells to enter the S-phase.
As the other early gene product of BKPyV, tiny tAg, inhibits protein phosphatase 2A (PP2A), a crucial tumor suppressor in several death-signaling pathways, it contributes to transformation.
In addition, animals injected with BKPyV frequently developed ependymomas, pancreatic islet tumors, osteosarcomas, fibrosarcomas, liposarcomas, osteosarcomas, nephroblastomas, and gliomas
Early research demonstrated that the kidney and urinary system can get infected with BKPyV, which can cause a chronic or latent infection.
Thus, carcinomas that impact this anatomical region are probably candidates for correlations with BKPyV.
Prostatic cancer, urothelial bladder cancer, and renal cancer have all been the subject of in-depth research.
It is unclear how much BKPyV contributes to the genesis of bladder cancer in immunocompetent people.
However, some data suggest a connection between BKPyV and metastatic bladder cancer in transplant patients who have immunosuppressed bodies.
The association between BKPyV infection and prostate cancer (PCa), one of the main causes of cancer-related deaths in men globally, has been researched by numerous organizations in recent years.
Conclusion
Further research is needed to confirm or disprove BKPyV’s involvement in tumor development.
Further research is needed to determine if additional factors (like host-related variables, infectious pathogens, or environmental components) can cause cancer.
This article address the molecular mechanisms of BKPyV infection and its potential association with cancer.
BK virus is Human polyomaviruses (HPyVs) are small, non- enveloped, dsDNA viruses.
The HPyV genome encodes early small-t/large-T antigens as well as late structural proteins called VP1, VP2, VP3, and agno- protein.
The early region transcript before DNA replicate consist of large T and small t antigen genes.
The late region is transcribed concomitant with DNA replication.
The agnoprotein is expressed from the region of VP2 and it’s responsible for control of HPyV life cycle.
It’s occur in early life from feco- oral transmission.
There’s Four polyomaviruses that show evidence of oncogenic potential — SV40, BKPyV, JCPyV, and MCPyV and there’s strong association with developing of cancer especially skin cancer and Merkel cell carcinoma.
The SV40 is suspected to be association with cancer but still under studies. Tropism and epidemiology:
The primary infection mainly occurs in early childhood, with a seroprevalence of 65–90% in 5–9 year- old children.
If the patients becomes immunocompromised the primary infection will be persist in the kidney and causes significant morbidity. The BKPyV may causes hemorrhagic cystitis in bone marrow transplant and BK nephropathy in renal transplant patients.
The virus presents in almost of tissue and mode of transmission by feco oral and many studies shows vertical transmission in seronegative pregnant women.
There’s strong evidence of oncogenic activity of BKPyV but still upto now no conclusive relationship between BKPyV and cancer and it’s may be due to presence of reasons as fallow//
First: the viral agent has a high prevalence in the general population;
Second: there are a wide distribution of virus to human tissues
Third: the virus has the ability to remain in a latent state for long periods, with occasional reactivations. Role in carcinogenesis:
The oncogenic genes of BK V are well demonstrated in vitro and vivo experimental models.
The transforming activity is recognised in the early region of the BKPyV genome, which encodes two viral oncoproteins: the large T-antigen (TAg) and the small t-antigen (tAg). This oncoprotein bind to different cellular proteins in different tissue of body and any alteration of these function may predispose to formation of cancer.
Many studies shows that BKPyV is highly oncogenic in rodents. They showed injected animal with BKPyV frequently developed ependymomas, pancreatic islet tumors, osteosarcomas, fibrosarcomas, liposarcomas, osteosarcomas, nephro- blastomas and gliomas.
Experimental study done for mice to express transgenic BKPyV shows early genome region were develop highly tissue specific tumors.
Few studies shows these animals developed primary hepatocellular carcinomas and renal tumors, thymuses and renal adenocarcinomas.
BK V TAg may lead to random mutational events which activate cellular oncogenes or inactivate other tumor suppressor genes.
However, some studies shows no association between BKPyV DNA and tumors.
There’s many conflict studies regarding the role of BKPyV in bladder cancer. Prostatic cancer are common cancer in male and it’s relation with BKV still under studies.
Conclusion:
The role of BKV in developing of cancer still under studying and still not proved. So it’s need further experimental studies.
What is the level of evidence provided by this article?
Human polyomaviruses are small, non-enveloped, double-stranded DNA viruses with 5000-bp genome and icosahedral symmetry.
They encode early small-t/large-T antigens and late structural proteins called VP1, VP2, VP3, and agno-protein.
A non-coding control region (NCCR) is located between the oppositely-oriented transcriptional units.
BKPyV is involved in regulating viral gene expression and maturating HPyV, and it relation to various cancer.
Viral entry
By BKPyV infection, VP1 interacts with the α2, 8- SA-containing b-series gangliosides (GD1b/GT1b) for cell attachment, forming a crystal like complex of VP1, and the ganglioside GD3 is formed.
This contact is essential for virus infection and is caveolin (involved in BKPyV entry) and clathrin (endocytic pathway).
After entering the cell, the virus must reach the nucleus via the importin-α/β pathway, guided by nuclear localization signals.
Tropism and epidemiology
BKPyV infection is 65-90% prevalent in 5-9 year-old children.
It causes hemorrhagic cystitis and Nephropathy in bone marrow and renal transplant patients, and is transmitted through fecal oral transmission.
It was reported the presence of BKPyV in 7 out 10 specimens of aborted fetuses suggesting the possibility of transplacental transmission( vertical transmission).
Permissive cells for viral replication are kidney cells, and non permissive cells, BKPyV lytic replication is blocked, and abortive infection may result in oncogenic transformation.
However, this relationship is difficult to demonstrate in ecological contexts for several reasons:
1. The virus is highly prevalent in the general population. 2. Wide range of human tissues were the virus can be detected. 3. The ability of the virus to remain in a latent state for long periods, with occasional reactivations.
Role in carcinogenesis
BKPyV is an oncogenic virus that induces cell immortalization and neoplastic transformation in embryonic fibroblasts and mouse cells, suggesting a cooperative effect of two oncogenes in early carcinogenesis.
KPyV large TAg is a highly multifunctional protein that can bind various cellular proteins, altering signaling pathways involved in cell cycle control( p53, and pRb) The interaction between BKPyV TAg and p53 results in the inactivation of this protein, interfering with the response to DNA damage and inducing the unscheduled onset of the S-phase
Small tAg plays an important role in transformation by inhibiting protein phosphatase 2A, a tumor suppressor in numerous death-signaling pathways.
Small et al. showed primary hepatocellular carcinomas and renal tumors.
Dalrymple and Beemon observed enlarged thymuses and renal adenocarcinomas.
BKPyV TAg activity is lower in BSC-infected BSC cells than the TAg activity expressed by the SV40 virus under the same conditions, suggesting that additional events are needed for complete transformation.
BKPyV TAg binds to or inactivates tumor suppressor proteins, leading to cellular oncogene activation and chromosomal instability in human embryonic fibroblasts.
BKPyV has been detected, human tumors, including brain tumors, osteosarcomas, Ewing’s tumors, neuro-blastomas and genitourinary tract tissues tumors.
BKPyV, may be a cofactor of tumors.
Recent reports have documented the presence of BKPyV DNA in association with HPV16 in high-grade cervical squamous intraepithelial lesions, suggesting that this virus could be involved in HPV16-induced cell trans-formation.
BKPyV has been linked to the etiology of bladder cancer in immunocompetent individuals, but its role is not well established.
Roberts et al. reported that while no positive BKPyV TAg urothelial carcinomas were found in a series of non-transplanted patients, strong nuclear staining for TAg was seen in one renal transplant patient.
Chen et al. found that 6/864 patients developed polyomavirus-associated nephropathy (PVAN).
The patients who develop PVAN are at incraesed risk of developing cancers, including transitional cell bladder carcinoma.
Prostate cancer (PCa) is one of the leading causes of cancer deaths in men worldwide, and its relationship with BKPyV infection has been studied by several groups in recent years.
The virus is dispensable at late stages of the disease and may be cleared from the lesion.
A “hit-and-run” carcinogenesis mechanism, but is difficult to defend experimentally.
Conclusion Ability of interaction of BKPyV with other host-related factors, infectious agents or environmental components for carcinogenesis, and needs more investigation, and studies.
What is the level of evidence provided by this article The level of evidence provided by this article V- erratic review
I agree with your analysis, summary and level of evidence this article provides.I appreciate your views on carcinogenic potential of BKV. The word ‘Narrative review’ has been mistyped in your last sentence
HPyVs are small, non enveloped, double-stranded DNA viruses with 5000-bp genome and icosahedral symmetry.
They encode early small-t/large-T antigens and late structural proteins called VP1, VP2, VP3, and agno-protein.
A non-coding control region (NCCR) is located between the oppositely-oriented transcriptional units.
BKPyV is involved in regulating viral gene expression and maturating HPyV.
HPyVs are ubiquitous and have been linked to various pathologies, with four polyomaviruses showing oncogenic potential. This review evaluates the molecular mechanisms of BKPyV infection and its potential association with cancer.
BKPyV infection involves a crystal-like complex of VP1 and GD3 forming a contact between VP1 and two sialic molecules of a disia-lic acid ganglioside.
This contact is essential for virus infection and is caveolin- and clathrin-independent.
After entering the cell, the virus must reach the nucleus via the importin-α/β pathway, guided by nuclear localization signals.
Tropism and epidemiology
BKPyV infection is a widely-distributed strict anthropo-nosis,with a seroprevalence of 65-90% in 5-9 year-old children.
It causes hemorrhagic cystitis and Nephropathy in bone marrow and renal trans-plant patients, and is transmitted through fecal-oral transmission.
PBLs transport BKPyV to different sites and organs, suggesting transplacental transmission.
BKPyV infection in a permissive host cell leads to DNA replication, production of progeny viral particles, and cell death.
BKPyV has a high prevalence in the general population, a wide range of tissues, and the ability to remain latent for long periods with occasional reactivations.
BKPyV is an oncogenic virus that induces cell immortalization and neoplastic transformation in embryonic fibroblasts and mouse cells, suggesting a cooperative effect of two oncogenes in early carcinogenesis.
KPyV large TAg is a multifunctional protein that can bind various cellular proteins, altering signal-ing pathways involved in cell cycle control.
It interacts with p53 and pRb, leading to the release and nuclear translocation of transcription factors and subsequent expression of genes.
Small tAg plays an important role in transformation by inhibiting protein phosphatase 2A, an essential tumor suppresor in numerous death-signaling pathways.
BKPyV is highly onco-genic in rodents, with tumors at various locations and tissue-specific alterations.
Small et al. showed primary hepatocellular carcinomas and renal tumors.
Dalrymple and Beemon observed enlarged thymuses and renal adenocarcinomas.
BKPyV is well-documented in experimental rodent models, but its transforming ability is not always observed in human and primates.
It is not efficient and is often abortive, and features of the transformed phenotype are not fully displayed.
BKPyV TAg activity is lower in BSC-infected BSC cells than the TAg activity expressed by the SV40 virus under the same conditions, suggesting that additional events are needed for complete transformation.
Integration of early-region viral sequences into the host genome has been shown to account for the difference between serum-independent growth and full transformation in human embryonic kidney cells, leading to increased expression of early genes and a consequent increase in transforming activity.
BKPyV TAg binds to or inactivates tumor suppressor proteins, leading to cellular oncogene activation and chromosomal instability in human embryonic fibroblasts.
BKPyV has been detected in a wide range of human tumors, including brain tumors, osteosarcomas, Ewing’s tumors, neuro-blastomas and genitourinary tract tissues tumors.
It may not be directly involved in the development of cancer, but may play a role as a co-factor in the carcinogenic process.
Recent re-ports have documented the presence of BKPyV DNA in association with HPV16 in high-grade cervical squamous intraepithelial lesions, suggesting that this virus could be involved in HPV16-induced cell trans-formation.
Further experimental studies and clinical observations are needed to verify this putative transformation mechanism.
BKPyV has been linked to the etiology of bladder cancer in immunocompetent individuals, but its role is not well established.
Roberts et al. reported that while no positive BKPyV TAg urothelial carcinomas were found in a series of non-transplanted patients, strong nuclear staining for TAg was seen in one renal transplant patient.
In a retrospective review of kidney transplant patients, Chen et al. found that 6/864 patients developed polyomavirus-associated nephropathy (PVAN).
This suggests that patients who develop PVAN are at a significantly higher risk of developing cancers, including transitional cell bladder carcinoma.
BKPyV codes a pre-miRNA hairpin at the 3′ end of the late gene coding region, which may be functional during infection and contribute to BKPyV-mediated cell transformation.
Prostate cancer (PCa) is one of the leading causes of cancer deaths in men worldwide, and its relationship with BKPyV infection has been studied by several groups in recent years.
Monini et al. and Das and Russo found similar detection rates in PCa cases, with a significantly lower prevalence in controls.
However, other authors disagree with these results, with Lau et al. detecting only 2/30 prostatic adenocarcinomas and no TAg expression in neoplastic tissue.
Sfanos et al. of 338 analyzed total samples from 200 patients detected only one positive sample.
This suggests that the virus is dispensable at late stages of the disease and may be cleared from the lesion.
BKPyV has been observed to colocalize in the cytoplasm, suggesting a tumorigenic mechanism in which the TAg inactivates p53 in the atrophic cells, increasing susceptibility to genetic alterations that may result in early prostate cancer progression.
This model is consistent with a “hit-and-run” carcinogenesis mechanism, but is difficult to defend experimentally.
Human polyomaviruses is dsDNA virus, its genome codes for early region antigen (t and T antigen and late (VP1, VP2 and VP3 )antigen and agnoprotein which is involved in various functions related to the HPyV life cycle, such as regulating viral gene expression or inducing viral maturation
Infection occur mostly early childhood and become latent with the mode of transmission is mainly fecooral root and there is evidence of transplacental transmission as well
Four polyomaviruses have been found to be carcinogenic — SV40, BKPyV, JCPyV, and MCPyV — which is linked to Merkel cell carcinoma
Tropism and Epidemiology
· As stated above infection started early in childhood by age of 9 > 90 % get infected
· After infection virus become dormant in kidneys ( its cell permit viral replication and called permissive cells )and various tissue ( liver , stomach, cervix , vulva , vagina , bladder, lips and tongue
· Under immunosuppression status, it regains activity and may cause BKVAN in kidney transplant and hemorrhagic cystitis in HSCT
· In a non-permissive cell, BKPyV lytic replication is blocked, and abortive infection may result in oncogenic transformation
Role in carcinogenesis
The rule of BKPyV as carcinogenic factor proved both in vitro and in vivo. it is related for early antigen region ( t and T ) which alter cell cycle and immortalize the cell and cause oncogenic transformation.
BKPyV large Tag has the ability of binding various cell protein interrupting normal cell cycle like P53 and bRp protein leading to their in activation hence leading the cell to enter into S- phase and this favors the accumulation of genetic alterations during each cell replication cycle
Additionally, the interaction between BKPyV TAg and pRb leads to the release and nuclear translocation of the E2 factor (E2F) family of transcription factors and subsequent expression of genes, inducing quiescent cells to enter the S-phase
On the other hand, The small tAg, inhibit protein phosphatase 2A (PP2A), an essential tumor suppressor in numerous death-signaling pathways and can activate signaling pathways that promote cell proliferation, such as mitogen-activated protein kinase (MAPK)
So, animals injected with BKPyV frequently developed ependymomas, pancreatic islet tumors, osteosarcomas, fibrosarcomas, liposarcomas, osteosarcomas, nephroblastomas and gliomas, primary hepatocellular carcinomas and renal tumors in Small trials while in Dalrymple and Beemon trial they report enlarged thymuses and renal adenocarcinomas.
In human this transforming activity is not always observed as had been identified in SV40 virus oncogenicity that may be explained by lower expression levels of the BKPyV promoter and enhancer elements, which share only 40% homology with the SV40 promoter region
Oncogenicity that occasionally happen with BCV may be de to p53 inactivation by BK TAg may lead to random mutational events that could activate cellular oncogenes or inactivate
The finding of the virus in tumor tissue does not mean its involvement in its development but may act as a co-factor in the carcinogenic process for example, recent reports have documented the presence of BKPyV DNA in association with HPV16 in high-grade cervical squamous intraepithelial lesions
The propensity of the BKV to urothelial cells raise the question of its involvement in the tumorigenesis .in a retrospective review by Chen et al. reported that 6/864 patients developed polyomavirus-associated nephropathy (PVAN). Malignancy occurred in 5/6 PVAN patients, suggesting that patients who develop PVAN are at significantly higher risk of developing cancers, including transitional cell bladder carcinoma in addition , These tumors are high-grade and invasive
Regarding involvement of BKV in prostatic cancer reports are contradictory but it has been postulated that BKPyV constitutes an important factor for early prostate tumorigenesis through early suppression of P 35 and bRp poteins
Conclusion
more epidemiological and experimental studies are strongly required to confirm or exclude the role of BKPyV in the development of tumors.
Human polyomaviruses are small DNA viruses have been found in human tumors and etiological relationship was proven with Merkel cell polyomavirus which linked to rare skin cancer, Merkel cell carcinoma (MCC). KPyV-mediated human carcinogenesis.
BKPyV structure and its function:
· Early Large Tumour Antigen (Tag): Cell cycle progression, inhibition of apoptosis, viral
replication.
· Minor T Antigen (tAg): Cell cycle progression.
· 3p-miRNA and 5p-miRNA: viral persistence.
· Late VP1: capsid structure (external), viral attachment and entry.
· VP2, VP3 capsid structure (internal): involved in viral infectivity.
· Agno protein Life cycle: assembly, maturation, release.
Although the oncogenic activity of BKPyV is proven in laboratory settings, there is no conclusive evidence of a causal relationship between BKPyV and cancer in human. This relationship is difficult to proven as:
1. high prevalence of the virus in the general population with no associated malignancy.
2. a wide range of human tissues in which the virus can be detected.
3. the virus has the ability to remain in a latent state for long periods.
4. the virus may co-infect cells that were previously infected by another oncogenic virus like HTLV-I, HCV, HPV, EBV, HHV-8 and HBV, increasing susceptibility to cancer
The oncogenic properties of BKPyV are well-demonstrated in in vitro and in vivo experimental
models.There are two viral oncoproteins: the large T-antigen (TAg) and the small t-antigen (tAg). These viral products induce alterations in the normal cell cycle, ultimately leading to cell immortalization and neoplastic transformation
· BKPyV large TAg targets the p53 family proteins and pRb tumor suppressor proteins results in the inactivation of this protein causing DNA damage.
· BKPyV TAg drives the cell to override a key cell cycle check-point, favoring the accumulation of genetic alterations during each cell replication cycle.
· the small tAg inhibiting protein phosphatase 2A (PP2A), an essential tumor suppressor in numerous death-signaling pathways. In Vitro
cells cultured from kidney or brain tissues with complete or sub-genomic fragments of BKPyV DNA, containing the early coding region, lead to oncogene-induced neoplastic transformation In Vivo Animal studies:
BKPyV is highly oncogenic in rodent as inoculated with the virus showed developed tumors at various locations that contained BKPyV DNA sequences
animals injected with BKPyV frequently developed ependymomas, pancreatic islet tumors, osteosarcomas, fibrosarcomas, liposarcomas, osteosarcomas, nephroblastomas and gliomas. In humans:
definitive transforming activity is not always observed in human. The transformation by BKPyV is not efficient and is often abortive, and features of the transformed phenotype are not fully displayed BCS: BKPyV TAg activity is lower in BKPyV-infected BSC cells and its expression by BKPyV is not sufficient to completely capture the Rb family of proteins bladder carcinoma:
in a retrospective review of kidney transplant patients on 6/864 patients developed polyomavirus-associated nephropathy (PVAN). Malignancy occurred in 5/6 PVAN patients suggesting that patients who develop PVAN are at significantly higher risk of developing cancers
in a multi-center study done on 114 transitional bladder carcinoma cases and a group of 140 hospital controls which showed no role of BKPyV in bladder cancer among immunocompetent individuals. Prostate cancer (PCa):
Prevalence study done by Monini et al. detected BKPyV in approximately 60% of cancerous and healthy prostates,and the viral load was found to be significantly higher in neoplastic as compared to non-neoplastic tissue.
Lau et al., using in situ, detected BKPyV in only 2/30 prostatic adenocarcinomas, and no TAg expression was detected in neoplastic tissue.
Similarly, Sfanos et al. of 338 analyzed total samples from 200 patients for BKPyV DNA and detected only one positive sample. Conclusion
BK virus relation to human malignancies like bladder and prostatic cancer is not proven yet and more epidemiological and basic research is still needed.
Human Polyomavirus HPvY has been associated with development of malignancies. HPyY has been associated with skin cancer and , Merkel cell carcinoma (MCC). This review is about the BK virus BKPyV infection from a historical point of view, including biological aspects related to viral entry, tropism, epidemiology and mechanisms potentially involved in BKPyV-mediated human carcinogenesis.
Tropism and epidemiology
The primary infection most often occurs in early childhood, with a seroprevalence of 65–90% in 5–9 year old.
Following primary infection, BKPyV persists in the kidneys. If the host becomes immunosuppressed, the virus causes significant morbidity.
Transmission can be feco oral, trnasplacental or by vertical route.
Currently there no significant evidence of association with BKPyV and malignancy.
Role in development of malignancy
The oncogenic properties of BKPyV are welldemonstrated in in vitro and in vivo
Two viral oncoproteins: the large T-antigen (TAg) and the small t-antigen (tAg)
The interaction between BKPyV TAg and p53 results in the inactivation of this protein, interfering with the response to DNA damage and inducing the unscheduled onset of the S-phase
Transforming ability of BKPyV is welldocumented in experimental rodent models, definitive transforming activity is not always observed in human
Inactivation of tumour suppressor gene has a role .
Alteration in chromosomal activity
Main association with bladder and prostate cancer.
Conclusion
· At the moment there is no conclusive evidence of role of BKPyV in the development of cancer
· The investigative strategies that might lead to conclusive evidence that would allow us to confirm or exclude the role of BKPyV in the development of tumours are required
☆Role of BK human polyomavirus in cancer ____________________________________
▪︎This review evaluated the molecular mechanisms of BKPyV infection and its potential association with cancer.
◇ Background ▪︎Human polyomaviruses (HPyVs) are small, nonenveloped, double-stranded DNA viruses belong to the polyomaviridae family. ▪︎In natural hosts, HPyVs establish a productive infection, while in heterologous, non-permissive hosts, the virus establishes latency with potential integration into the host genome. HPyV infection typically occurs early in life, often through fecal-oral transmission, and persists throughout the lifespan. ▪︎Fourteen HPyVs have been described, four of them have been found to show oncogenic potential — SV40, BKPyV, JCPyV, and MCPyV — although there is strong evidence of such a link only in the case of MCPyV in a rare skin cancer, Merkel cell carcinoma. ▪︎A carcinogenic role has also been suspected for SV40, but the association remains controversial. BK virus ▪︎A specific contact is essential for virus infection. ▪︎ After entering the cell, the virus must reach the nucleus for replication. The primary infection most often occurs in early childhood, with a seroprevalence of 65–90% in 5–9 yearold children. Following primary infection, BKPyV persists in the kidneys. ▪︎If the host becomes immunosuppressed, the virus causes significant morbidity. It is transmitted by fecal-oral and vertical Upon BKPyV infection in a permissive host cell, early gene expression leads to DNA replication, followed by late gene expression, production of progeny viral particles and cell death. Permissive cells for viral replication are kidney cells. In addition, it has been reported that some salivary glands cells are permissive for
◇ BKPyV infection ▪︎ In a non-permissive cell, BKPyV lytic replication is blocked, and abortive infection may result in oncogenic transformation. ▪︎Although the oncogenic activity of BKPyV is well documented in laboratory settings, there is no conclusive evidence of a causal relationship between BKPyV and cancer in human beings. This relationship is difficult to demonstrate in ecological contexts for several reasons: 1. The viral agent has a high prevalence in the general population. 2. There are a wide range of human tissues in which the virus can be detected. 3. The virus has the ability to remain in a latent state for long periods, with occasional reactivations. ◇ Role in carcinogenesis ▪︎The transforming activity of the BK virus has been mapped in the early region of the BKPyV genome, which encodes two viral oncoproteins: 1. The large T-antigen (TAg) 2. The small t-antigen (tAg) ▪︎These viral products induce alterations in the normal cell cycle, ultimately leading to cell immortalization and neoplastic transformation. ▪︎BKPyV large TAg can bind various cellular proteins (eg: p53), altering signaling pathways involved in cell cycle control. In addition, it can induceg quiescent cells to enter the S-phase by interaction with pRb ▪︎ The small tAg, inhibit the tumor suppressor protein phosphatase 2A (PP2A), ▪︎Although the transforming ability of BKPyV is well documented in experimental rodent models, definitive transforming activity is not always observed in human and primates. ▪︎Integration of early-region viral sequences into the host genome has been shown to account for the difference between serum-independent growth and full transformation in BKPyV-infected human embryonic kidney cells. ▪︎P53 inactivation by BK TAg may lead to random mutational events that could activate cellular oncogenes or inactivate other tumor suppressor genes. ▪︎Various authors have detected BKPyV genetic material in a wide range of human tumors (brain tumors, osteosarcomas, Ewing’s tumors, neuroblastomas and genitourinary tract tissues tumors, including prostatic and bladder cancers. In contrast, other authors reported no association between BKPyV DNA and tumors. ▪︎The virus may play a role as a co-factor in the carcinogenic process. ▪︎The contribution of BKPyV to the etiology of bladder carcinoma in immunocompetent individuals is not well established. On the other hand, there are reports that link BKPyV with metastatic bladder carcinoma in immunosuppressed transplant recipients. strong nuclear staining for TAg was seen in the urothelial carcinoma of one renal transplant patient. ▪︎Patients who develop PVAN are at significantly higher risk of developing cancers, including transitional cell bladder carcinoma. ▪︎BKPyV constitutes an important factor for early prostate tumorigenesis. But ispite of all The carcinogenic role of this virus has been difficult to demonstrate.
◇ Conclusion ▪︎This review explores the BKPyV infection from a historical point of view, including biological aspects related to viral entry, tropism, epidemiology and mechanisms potentially involved in BKPyV-mediated human carcinogenesis. ▪︎ In order to clarify the role of this virus in human cancer, more epidemiological and basic research is strongly warranted.
BKV is a small DNA virus that is widely distributed in the environment.
it is sometimes present in human tumors suggesting a causal relationship with malignancy. an example is the Merkel cell polyomavirus which is linked to Merkel cell carcinoma.
in 2012, the international agency for research on cancer evaluated the carcinogenicity of BKV and reported that BKV is possibly carcinogenic to humans.
the oncogenic properties of BKV are well-demonstrated in Vitro and in Vivo experimental models.
the transforming activity of BKV has been mapped to the early region of the virus genome that encodes 2 viral oncoproteins, named large T-antigen and small T-antigen.
the oncogenic activity is related to alterations in the normal cell cycle, leading to cell immortalization and neoplastic transformation.
a possible interaction with other factors is suggested for the development of human malignancies. these factors include host-related factors, infectious agents, and environmental factors.
more epidemiological and experimental studies are strongly required for full understanding the pathogenic role of BKV in human cancers.
What is the level of evidence provided by this article?
I agree with your analysis, summary and level of evidence this article provides.
I wish you could type headings and sub-headings as underline or in bold.
Human polyomaviruses (HPyVs) are small, non- enveloped, double-stranded DNA viruses.
The HPyV genome encodes early small-t/large-T antigens as well as late structural proteins called VP1, VP2, VP3, and agnoprotein.
These viruses also encode a pre-miRNA for generation of two mature miRNAs.
A non-coding control region (NCCR) regulate gene expression and harbors the replication origin.
In natural hosts, HPyVs establish a productive infection, while in non-permissive hosts, the virus establishes latency with potential integration into the host genome.
Four polyoma viruses have been found to show oncogenic potential — SV40, BKPyV, JCPyV.
MCPyV appears to play a role in a rare skin cancer, Merkel cell carcinoma.
Viral entry:
BKPyV utilizes an endocytic pathway, that is caveolin- and clathrin-independent and doesn’t involve alternative other known endocytic pathways.
After entering the cell, the virus must reach the nucleus for replication.
The virus enters the nucleus via the importin-α/β pathway, guided by nuclear localization signals present in the minor capsid proteins VP2 and VP3.
Tropism and epidemiology
The primary infection most often occurs in early childhood, with a sero-prevalence of 65–90% in 5–9 year old children.
Following primary infection, BKPyV persists in the kidneys.
If the host becomes immunosuppressed, the virus causes nephropathy (BKAN) in renal transplant patients.
BKPyV genomes have also been detected in liver, stomach, lungs, parathyroid glands, brain, bladder, uterine cervix and prostate .
Fecal-oral transmission is highly suggested and vertical transmission as well.
Permissive cells for viral replication are kidney cells, primary human renal proximal tubule epithelial cells and some salivary glands cells.
In a non-permissive cell, BKPyV replication is blocked, and abortive infection may result in oncogenic transformation.
The oncogenic activity of BKPyV is well documented in laboratory settings.
There is no conclusive evidence of a causal relationship between BKPyV and cancer in human beings.
Role in carcinogenesis
The transforming activities are related to the large T-antigen (TAg) and the small t-antigen (tAg).
The oncogenic antigens induce alterations in the normal cell cycle, ultimately leading to cell immortalization and neoplastic transformation.
BKPyV large TAg can bind various cellular proteins, altering signaling pathways involved in cell cycle control.
The interaction between BKPyV TAg and p53 in one hand and between BKPyV TAg and pRb in the other hand induces the unscheduled onset of the S-phase.
The small tAg, plays an important role in transformation by inhibiting protein phosphatase 2A (PP2A), an essential tumor suppressor in numerous death-signaling pathways.
Reports demonstrated that BKPyV is highly oncogenic in rodents, these animals developed tumors at various locations that contained BKPyV DNA sequences when inoculated with the virus.
Although the transforming ability of BKPyV is well documented in experimental rodent models, definitive transforming activity is not always observed in human.
Suggested model in humans is that in addition to BKPyV TAg modulating cellular growth , additional events are required for complete transformation. These events could be mutations or alterations of the viral promoter enhancer elements.
An alternative model for the role of BKPyV TAg in oncogenesis involves the first step in which BKPyV TAg binds to or inactivates tumor suppressor proteins, with a second step leading to cellular oncogene activation.
Moreover, it has been shown that BKPyV TAg induces chromosomal instability in human embryonic fibroblasts.
The early BKPyV genome region has been detected in brain tumors, osteosarcomas, Ewing’s tumors, neuroblastomas and genitourinary tract tissues tumors, including prostatic and bladder cancer in some studies.
In contrast, other authors reported no association between BKPyV DNA and tumors.
The mere presence of BKPyV DNA does not necessarily reflect a neoplastic involvement of the virus.
BKPyV may not be directly involved in the development of cancer, but instead, play a role as a co-factor in the carcinogenic process.
HPyVs have been detected in various tissues that are susceptible to transformation by HTLV-I, HCV, HPV, EBV, HHV-8 and HBV. There for the may increase susceptibility to cancer by co- infecting cells that were previously infected by another oncogenic virus.
Recent reports have documented the presence of BKPyV DNA in association with HPV16 in high-grade cervical squamous intraepithelial lesions.
Since BKPyV has a tropism for cell in kidney and urinary tract, carcinomas that affect this anatomical zone are likely candidates for associations with BKPyV.
There are reports that link BKPyV with metastatic bladder carcinoma in immunosuppressed transplant recipients.
Malignancy occurred in 5/6 PVAN patients, suggesting that patients who develop PVAN are at significantly higher risk of developing cancers, including transitional cell bladder carcinoma.
Recent studies demonstrating the relationship with BKPyV infection and prostatic cancer are conflicting.
p53 and pRb proteins are implicated in prostate Ca, there is a low incidence of mutations in these genes during early stages of the disease.
Conclusion:
There is no conclusive evidence that would allow for confirmation or exclusion of the role of BKPyV in the development of tumors.
More epidemiological and experimental studies are strongly required.
The possibility of interaction with other host-related factors, infectious agents or environmental components for carcinogenesis needs more investigation.
Summary of This Article. Human polyomaviruses are small, nonenveloped, double-stranded DNA viruses belong to the polyomaviridae family are prevalent in human populations. there genome encodes have early coding region, late coding region
and non-coding control region NCCR.
Around 14 poliomaviruses have been discovered.
Four viruses have been found to have oncogenic potential — SV40, BKPyV, JCPyV, and MCPyV.
Both Skin cancer and Merkel cell carcinoma are strongly linked to MCPyV.
Some of these viruses have been discovered in human malignancies, indicating an
etiological link between these viruses and cancer.
BKPV virus was assessed for carcinogenicity by the International Agency for Research
on Cancer (IARC) in 2012, & IARC concluded that BKPV is “possibly carcinogenic to
humans.”
More epidemiological & basic research is required to uncover the part played by this
virus in human cancer.
BKV:
The primary infection most often occurs in early childhood, with a seroprevalence of 65–90% in 5–9-year-old children.
Following primary infection, BKV persists in the kidneys.
BKV genome can be detected in liver, stomach, lungs, parathyroid glands, lymph nodes, brain, peripheral blood mononuclear cells, bladder, uterine cervix, vulva, prostate, lips, and tongue.
Upon BKV infection in a permissive host cell (Kidney and salivary gland), early gene expression leads to DNA replication, followed by late gene expression, production of progeny viral particles and cell death.
In a non-permissive cell, BKV lytic replication is blocked, and abortive infection may result in oncogenic transformation.
Although the oncogenic activity of BKV is well documented in laboratory settings, there is no conclusive evidence of a causal relationship between BKV and cancer in human beings.
The BKPV Genome
The BKPV’s genome is a closed circular, ds DNA molecule of 5 kb. The origin of replication drives the bidirectional transcription of early & late coding regions (NCCR).
The early coding region is responsible for encoding the mRNAs that result in the big tumour antigen (Tag), small tumour antigen (tAg), & truncated TAg.
The structural proteins VP1, VP2, & VP3, & Agno protein are encoded in the late coding area
Function of BKPV gene products:
The early region products drive the cell cycle progression, inhibition of apoptosis, viral replication, and viral persistence.
The late region products drive capsid structure, viral attachment & entry, viral infectivity, and life cycle (assembly, maturation, release).
Oncogenicity:
Four polyomaviruses, SV40, BKPV, JCPV and MCPV, exhibit carcinogenic potential; however, only MCPV has a strong relationship to cancer.
SV40 has also been linked to a potential carcinogenic role, however no robust data to support this claim.
Role of BKPV in carcinogenesis:
The transforming activity has been mapped in the early region of the BKPV genome, which encodes two viral oncoproteins: Tag and tAg.
BKPV is highly oncogenic in rodents. BKPV DNA sequences were found in tumors in newborn hamsters, mice, & rats that had been infected with the virus.
Conclusive transforming activity is not always seen in humans & other primates.
BKPV genetic material has been detected in many human tumors: brain tumors, osteosarcomas, Ewing’s tumors, neuroblastomas, prostatic, & bladder cancer.
However, this does not necessarily reflect a neoplastic involvement of the virus.
BKPV may co-infect cells that were previously infected by another oncogenic virus (HTLV-I, HCV, HPV, EBV, HHV-8 & HBV).
Monini et al. detected BKPV in approximately 60% of cancerous & healthy prostates.
Evidence of BKPV carcinogenicity
Viral oncogenes are expressed in tumors.
Tumors developed in in vivo models.
Transforming properties in in vitro models
BKPV alterations occur before immortalization.
BKPV genome detected in human tumors.
Evidence for a non-carcinogenic role
Poor & not efficient transforming activity in human cells
Ubiquitous distribution in normal human cells and tissues
Conclusion BKPyV may have a role in the development of tumors Further studies are strongly required
Other possible carcinogenic related factors (host-related factors, infectious agents, or environmental components) warrant more investigation The carcinogenic role of the virus is difficult to demonstrate for many reasons:
1- the viral agent has a high prevalence in the general populations
2- there are a wide range of human tissues in which the virus can be detected
3- The virus could remain in a latent state for long periods, with occasional reactivations. Level of evidence V => (Review article)
Some of these viruses have been discovered in human malignancies, indicating an etiological link between these viruses & cancer.
Merkel cell polyomavirus (MCC), a specific HPV, has compelling evidence of carcinogenicity. It has been linked to Merkel cell carcinoma (a rare skin cancer).
BKPV virus was assessed for carcinogenicity by the International Agency for Research on Cancer (IARC) in 2012, & IARC concluded that BKPV is “possibly carcinogenic to humans.”
More epidemiological & basic research is required to uncover the part played by this virus in human cancer.
The BKPV Genome
The BKPV’s genome is a closed circular, ds DNA molecule of 5 kb. The origin of replication drives the bidirectional transcription of early & late coding regions (NCCR).
The early coding region is responsible for encoding the mRNAs that result in the big tumour antigen (Tag), small tumour antigen (tAg), & truncated TAg.
The structural proteins VP1, VP2, & VP3, & Agno protein are encoded in the late coding area.
Function of BKPV gene products:
The early region products drive the cell cycle progression, inhibition of apoptosis, viral replication, & viral persistence.
The late region products drive capsid structure, viral attachment & entry, viral infectivity, & life cycle (assembly, maturation, release).
Oncogenicity:
Four polyomaviruses, SV40, BKPV, JCPV, & MCPV, exhibit carcinogenic potential; however, only MCPV has a strong relationship to cancer.
SV40 has also been linked to a potential carcinogenic role, however no robust data to support this claim.
Role of BKPV in carcinogenesis:
The transforming activity has been mapped in the early region of the BKPV genome, which encodes two viral oncoproteins: Tag & tAg.
BKPV is highly oncogenic in rodents. BKPV DNA sequences were found in tumors in newborn hamsters, mice, & rats that had been infected with the virus.
Conclusive transforming activity is not always seen in humans & other primates.
BKPV genetic material has been detected in many human tumors: brain tumors, osteosarcomas, Ewing’s tumors, neuroblastomas, prostatic, & bladder cancer.
However, this does not necessarily reflect a neoplastic involvement of the virus.
BKPV may co-infect cells that were previously infected by another oncogenic virus (HTLV-I, HCV, HPV, EBV, HHV-8 & HBV).
Monini et al. detected BKPV in approximately 60% of cancerous & healthy prostates.
Evidence of BKPV carcinogenicity
Viral oncogenes are expressed in tumors.
Tumors developed in in vivo models.
Transforming properties in in vitro models
BKPV alterations occur before immortalization.
BKPV genome detected in human tumors.
Evidence for a non-carcinogenic role
Poor & not efficient transforming activity in human cells
Ubiquitous distribution in normal human cells and tissues
Variable BKPV presence in tumors among different studies
============================= 2. What is the level of evidence provided by this article?
The role of the BK virus in cancer: Introduction: BK virus is a small DNA virus belonging to polyomavirus, and the primary infection most commonly happens in early pediatric age, but in immunocompetent population, it mostly doesn’t cause clinical disease, while in immunocompromised patient the dormant virus, replicate and reactivated and it may cause BK viremia and BKVN. Role in carcinogenesis:
The oncogenic properties of BKPyV are well-studied, and it shown to be highly oncogenic in rodents.
The transforming part is located in the early region of the BKPyV genome, which encodes two viral oncoproteins:
1. The large T-antigen (TAg). 2. The small t-antigen (tAg).
They induce alterations in the normal cell cycle, leading to cell immortalization and neoplastic transformation.
BKPyV large TAg is a highly multifunctional protein that can bind many cellular proteins, changing signaling pathways involved In the cell cycle control.
Most part studies in TAg are p53 family protein and pRb tumor suppressor proteins.
The interaction between BKPyV TAg and p53 results in the inactivation of this protein, interfering with the response to DNA damage and inducing the unscheduled onset of the S-phase.
Therefore, BKPyV TAg drives the cell to override key cell cycle checkpoints, which leads to the accumulation of genetic alterations during each cell replication cycle.
Added to this, the interaction between BKPyV TAg and pRb leads to the release and nuclear translocation of the E2 factors family of transcription factors and subsequent expression of genes, inducing quiescent cells to enter the S-phase.
The other early small tAg, play an important role in transformation by inhibiting protein phosphatase 2A (PP2A), an essential tumor suppressor in many death-signaling pathways, and by inhibiting this signaling pathway, the cell proliferation occur, such as mitogen-activated protein kinase (MAPK).
The contribution of BKPyV to the etiology of bladder carcinoma is not well-established.
Some studies demonstrate BKPyV DNA sequences in bladder carcinoma, but it was small case series that either lack of a control group or relies entirely on anti-body seroprevalence.
Pole-sel et al, a multicenter study, found similar prevalence of the viral DNA in a group 114 transitional bladder carcinoma csases and a group of 140 hospital control, but the result does not support the role of BKPyV in bladder cancer among immunocompetant individuals.
In immunosuppressed transplant recipients, they found a link between BKPyV with metastatic bladder carcinoma.
Roberts et al, found a strong nuclear staining for TAg was seen in urothelial carcinoma of one renal transplant patient, this indicate that the virus may have a tumorigenic role in some cases.
Chen et al. reported that 6/864 patients develop polyomavirus-associated nephropathy, malignancy occurred in 5/6 PVAN patients, suggesting that patients with PVAN are at high risk of developing cancer including transitional cell carcinoma.
Monini et al. detected BKPyV in 60% of cancerous and healthy prostate, and the viral load was found to be significantly higher in neoplastic as compared to non-neoplastic tissue.
Lau et al. Sfanos et al. and Chile group, the results was insignificant.
This contradictions are related to the variable sensitivity and specificity in different methods.
Conclusion:
Conclusive evidence was needed to allow confirmation or exclusion of the BKPyV in the development of tumor.
1-Please summarise this article? Introduction;.
-Human polyomaviruses (HPyV), which are small DNA viruses classified into the polyomaviridae family, are widely distributed in human populations.
-Thirteen distinct HPyVs have been described to date. Some of these viruses have been found in human tumors, suggesting an etiological relationship with cancer.
-In particular, convincing evidence of an oncogenic role has emerged for a specific HPyV, the Merkel cell polyomavirus (MCPyV). This HPyV has been linked to rare skin cancer, Merkel cell carcinoma (MCC).
-Four polyomaviruses have been found to show oncogenic potential — SV40, BKPyV, JCPyV, and MCPyV, Role in carcinogenesis;
-The oncogenic properties of BKPyV are welldemonstrated in in vitro and in vivo experimental models.
-The transforming activity has been mapped in the early region of the BKPyV genome, which encodes two viral oncoproteins: the large T-antigen (TAg) and the small t-antigen (tAg).
-These viral products induce alterations in the normal cell cycle, ultimately leading to cell immortalization and neoplastic transformation.
-In addition, the interaction between BKPyV TAg and pRb leads to the release and nuclear translocation of the E2 factor (E2F) family of transcription factors and subsequent expression of genes, inducing quiescent cells to enter the S-phase.
-Various authors have detected BKPyV genetic material in a wide range of human tumors.
-For instance, the early BKPyV genome region has been detected in brain tumors, osteosarcomas, Ewing’s tumors, neuroblastomas and genitourinary tract tissues tumors, including prostatic and bladder cancer.
-In contrast, other authors reported no association between BKPyV DNA and tumors. In any case, the mere presence of BKPyV DNA does not necessarily reflect a neoplastic involvement of the virus.
-The association of BKPyV with precancerous cervical lesions suggests that this virus could be involved in HPV16-induced cell transformation.
-The contribution of BKPyV to the etiology of bladder carcinoma in immunocompetent individuals is not well established. Some studies demonstrate BKPyV DNA sequences at high frequencies in bladder carcinoma.
-Prostate cancer (PCa) is one of the leading causes of cancer deaths in men worldwide, and its relationship with BKPyV infection has been studied by several groups in recent years. Conclusion;.
-The challenge now is to devise investigative strategies that might lead to conclusive evidence that would allow us to confirm or exclude the role of BKPyV in the development of tumors.
-Thus, more epidemiological and experimental studies are strongly required.
-In addition, the possibility of interaction with other host-related factors, infectious agents or environmental components for carcinogenesis warrants more investigation. 2-What is the level of evidence provided by this article? level V evidence.
Role of BK human polyomavirus in cancer. Background.
The HPyV genome encodes early small-t/large-T antigens as well as late structural proteins called VP1, VP2, VP3, and Agno protein.In BKPyV, JCPyV, and SV40, the Agno protein is expressed from the 5’region of VP2 open reading frame.
HPyV infection typically occurs early in life, often through fecal-oral transmission, and persists throughout the lifespan, Four polyomaviruses have been found to show oncogenic potential which are SV40, BKPyV, JCPyV, and MCPyV. This virus (MCPyV.) appears to play a role in a rare skin cancer, Merkel cell carcinoma. BK virus.
A specific contact between the terminal sialic acid residue of GD3 and VP1 is essential for virus infection, virus entry does not require actin polymerization, exclude other known alternative endocytic pathways and suggests that BKPyV utilizes an as-yetun characterized endocytic pathway.Finally, the virus enters the nucleus via the importin-!/” pathway, guided by nuclear localization signals present in the minor capsid proteins VP2 and VP3. Tropism and epidemiology.
The primary infection most often occurs in early childhood, with a seroprevalence of 65–90% in 5–9 year old children and then persists in the kidneys, later on it might cause hemorrhagic cystitis and nephropathy (BKAN) in bone marrow and renal transplant patients, transmitted by multiple routes such as faeco-oral, respiratory, organ transplantation, and Transplacental. Role in carcinogenesis.
The large T-antigen (TAg) and the small t-antigen (tAg). These viral products induce alterations in the normal cell cycle, ultimately leading to cell immortalization and neoplastic transformation, The most
frequently-studied cellular targets of TAg are the p53 family proteins and pRb tumor suppressor proteins and this lead to inducing the unscheduled onset of the S-phase, all theses experimental studies such as animals injected with BKPyV frequently developed ependymomas, pancreatic islet tumors, osteosarcomas, fibro sarcomas, lip sarcomas, osteosarcomas, nephroblastomas and gliomas.An alternative model for the role of BKPyV TAg in oncogenesis involves the first step in which BKPyV Tag binds to or inactivates tumor suppressor proteins, with a second step leading to cellular oncogene activation. It is controversial till now, Various authors have detected BKPyV genetic material in a wide range of human tumors . For instance, the early BKPyV genome region has been detected in brain tumors, osteosarcomas, Ewing’s tumors, neuroblastomas and genitourinary tract tissues tumors, including prostatic and bladder cancer . In contrast, other authors reported no association between BKPyV DNA and tumors, other theory that the association between oither oncogenic virus might be the cause of ontogenesis such as the association of BKPyV with precancerous cervical lesions suggests that this virus could be involved in HPV16-induced cell transformation. Some studies demonstrate BKPyV DNA sequences at high frequencies in bladder carcinoma but no large randomized control studies confirmed that, the relation between the BKPyV and cancer prostate is still controversial as a possible tumorigenic mechanism in which the TAg inactivates p53 in the atrophic cells, increasing susceptibility to genetic alterations, including tumor suppressor gene mutations that may result in early prostate cancer progression. Conclusion.
Still, there is no robust evidence about the role of BKPyV and progression of different types of tumors and its role in carcinogenesis and more investigational studies needed to confirm or exclude that.
Level of evidence:V.
The HPyV genome encodes for:
1. Early small-t/large-T antigens (transcribed before DNA replication begins)
2. Late structural proteins called VP1, VP2, VP3, and agnoprotein (transcribed concomitant with DNA replication.)
3. Pre-miRNA for generation of two mature miRNAs
Agnoprotein protein may be involved in various functions related to the HPyV life cycle, such as regulating viral gene expression or inducing viral maturation
Four polyomaviruses show oncogenic potential (SV40, BKPyV, JCPyV, and MCPyV)
Strong evidence of cancer link is only in MCPyV (Merkel cell carcinoma)
Aim of the study:
Address the molecular mechanisms of BKPyV infection and its potential association with cancer
Viral entry
· During BKPyV infection, VP1 interacts with gangliosides and the complex ganglioside GD3 is formed
· BKPyV utilizes an as-yetuncharacterized endocytic pathway
· After entering the cell, the virus reach the nucleus for replication [This process depends on acidification and maturation of the endosome and involves retrograde transit of endocytic vesicles to the endoplasmic reticulum (ER)]
· At the end, the virus enters the nucleus via the importin-α/β pathway, guided by nuclear localization signals present in the minor capsid proteins VP2 and VP3
Tropism and epidemiology
BKPyV genomes detected in kidney, bone marrow, liver, stomach, lungs, parathyroid glands, lymph nodes, brain, peripheral blood mononuclear cells, bladder, uterine cervix, vulva, prostate, lips and tongue
Route of transmission: fecal-oral transmission, vertical transmission (only in primary BKV infection), and transplacental
BKPyV infection in a permissive host cell: early gene expression leads to DNA replication, followed by late gene expression, production of progeny viral particles and cell death
Permissive cells are:
1. Kidney cells such as Vero (African green monkey kidney), HEK293 (human embryonic kidney cells) or RPTE (primary human renal proximal tubule epithelial cells)
2. Some salivary glands cells
Non-permissive cell: BKPyV lytic replication is blocked, and abortive infection may result in oncogenic transformation
The relationship between BKPyV and cancer in human is difficult to demonstrate because of:
1. The viral agent has a high prevalence in the general population
2. Second, there are a wide range of human tissues in which the virus can be detected
3. The virus has the ability to remain in a latent state for long periods, with occasional reactivations
Role in carcinogenesis
o The large T-antigen (TAg) and the small t-antigen (tAg) induce alterations in the normal cell cycle, and ultimately leading to cell immortalization and neoplastic transformation
o BKPyV large TAg is a highly multifunctional protein binds various cellular proteins, altering signaling pathways involved in cell cycle control (p53 family proteins and pRb tumor suppressor proteins)
o The small tAg, plays an important role in transformation by inhibiting protein phosphatase 2A (PP2A), an essential tumor suppressor in numerous death-signaling pathways
o Transforming in BKPyV is well documented in experimental animals, but definitive transforming activity is not always observed in human
o BKPyV has a tropism for certain cell types like kidney and urinary tract (so, renal cancer, urothelial bladder cancer, and prostatic cancer are likely associated)
Evidences of BKPyV carcinogenicity:
1. Viral oncogenes are expressed in tumors
2. Tumors developed in in vivo models
3. Transforming properties in in vitro models
4. BKPyV alterations occur before immortalization
5. BKPyV genome detected in human tumors
Evidences for a non-carcinogenic role:
1. Poor and not efficient transforming activity in human cells
2. Ubiquitous distribution in normal human cells and tissues
3. Variable BKPyV presence in tumors among different studies
Conclusion
· BKPyV may have a role in the development of tumors
· Further studies are strongly required
· Other possible carcinogenic related factors (host-related factors, infectious agents or environmental components) warrant more investigation
What is the level of evidence provided by this article?
Level V
Background
-Human polyomaviruses are small, nonenveloped, double-stranded DNA viruses belong to the polyomaviridae family. there genome encodes have
early coding region,
late coding region
and non-coding control region NCCR.
Around 14 poliomaviruses have been discovered.
Four viruses have been found to have oncogenic potential — SV40, BKPyV, JCPyV, and MCPyV.
-Both Skin cancer and Merkel cell carcinoma are strongly linked to MCPyV.
Viral entry A crystal-like complex of VP1 and ganglioside GD3 is formed with several points of contact between VP1 and two sialic molecules of a disialic acid ganglioside. This model was tested using site-directed mutagenesis. Using a siRNA strategy, it was demonstrated that BKPyV entry is caveolinand clathrin-independent. The virus must reach the nucleus for replication. This process depends on acidification and maturation of the endosome and involves retrograde transit of endocytic vesicles to the endoplasmic reticulum. The virus enters the nucleus via the importin-α/β pathway, guided by nuclear localization signals present in the minor capsid proteins VP2 and VP3. Role in carcinogenesis:
The oncogenic role was demonstrated in vivo and in vitro. Rodents infected with this virus showed the development of tumors at various locations that contained BKV DNA sequences, either integrated into the host genome or in a free episomal form with constitutive TAg expression. Experimental suggest that while BKV TAg may modulate cellular growth through direct interactions with critical regulatory proteins, additional events (mutations) are required for complete transformation. Also, they linked the transformation activites to the higher expression of Ha-ras oncogen and inactivation of P53 tumor suppressor gene. In human:
Various authors have detected the early BKV genome region in brain tumors, osteosarcomas, Ewing’s tumors, neuroblastomas and genitourinary tract tissues tumors, including prostatic and bladder cancer. The contribution of BKV to the etiology of bladder carcinoma in immunocompetent individuals is not well-established. Some linked it to metastatic disease In prostate cancer, some authors reported significantly higher expression of BKV presence in malignant cells compared to non-malignant cells. This was not proven in other cases. Based on genetic studies, some postulated that BKV infection implicated suppression of tumor suppressor genes. the TAg inactivates p53 in the atrophic cells, increasing susceptibility to genetic alterations, including tumor suppressor gene mutations that may result in early prostate cancer. In conclusion,
the carcinogenic role of the virus is difficult to demonstrate for many
reasons:
1- the viral agent has a high prevalence in the general populations
2- there are a wide range of human tissues in which the virus can be detected
3- The virus has the ability to remain in a latent state for long periods, with occasional reactivations.
Human polyomaviruses are small, nonenveloped, double-stranded DNA viruses with approximately 5000-bp genome and icosahedral symmetry.
These viruses belong to the polyomaviridae family.
The HPyV genome encodes early small-t/large-T antigens as well as late structural proteins called VP1, VP2, VP3, and agnoprotein.
The HPyV capsid harbors 72 pentamers of VP1, which interacts with the VP2/VP3 molecules associated with each pentamer .
These viruses encode a pre-miRNA for generation of two mature miRNAs.
Four polyomaviruses have been found to show oncogenic potential —SV40.BKPyV, JCPyV, and MCPyV — there is strong evidence of such a link only in the case of MCPyV
This virus appears to play a role in a rare skin cancer, Merkel cell carcinoma. This review evaluates the molecular mechanisms of BKPyV infection and its potential association with cancer Viral entry
A crystal-like complex of VP1 and the ganglioside GD3 is formed, with several points of contact between VP1 and two sialic molecules of a disialic acid ganglioside.
This model was tested using site-directed mutagenesis.
Using a siRNA strategy, it was demonstrated that BKPyV entry is caveolinand clathrin-independent.
The virus must reach the nucleus for replication.
This process depends on acidification and maturation of the endosome and involves retrograde transit of endocytic vesicles to the endoplasmic reticulum.
The virus enters the nucleus via the importin-α/β pathway, guided by nuclear localization signals present in the minor capsid proteins VP2 and VP3. Tropism and epidemiology
BKPyV infection is a widely-distributed strict anthroponosis.
The primary infection most often occurs in early childhood, with a seroprevalence of 65–90% in 5–9 year old children.
If the host becomes immunosuppressed, the virus causes significant morbidity.
BKPyV causes hemorrhagic cystitis and nephropathy (BKAN) in bone marrow and renal transplant patients, respectively.
BKPyV genomes have been detected in a wide spectrum of normal
BKPyV expression product function
Large tumor antigen Cell cycle progression, inhibition of apoptosis, viral replication truncated Large T antigen Cell cycle progression, viral replication.
The transmission mechanism is not completely elucidated, the high resistance of BKPyV to environmental inactivation and its presence at high concentrations in human sewage and other water sources suggest fecal-oral transmission.
In this respect, it was reported that salivary glands and oropharyngeal cells are not involved in BKPyV persistence, suggesting that digestive tract would be important for viral transmission.
Showed a vertical transmission of this virus only in the case of primary BKV infection of serologically negative pregnant women.
It was reported the presence of BKPyV in 7 out 10 specimens of aborted fetuses suggesting the possibility of transplacental transmission.
It has been reported that some salivary glands cells are permissive for BKPyV infection.
This relationship is difficult to demonstrate in ecological contexts for several reasons: first, the viral agent has a high prevalence in the general population; second, there are a wide range of human tissues in which the virus can be detected; and third, the virus has the ability to remain in a latent state for long periods, with occasional reactivations Role in carcinogensis
The oncogenic properties of BKPyV are well demonstrated in in vitro and in vivo experimental models.
These events could be mutations or alterations of the viral promoter enhancer elements, leading to increased expression of early genes and a consequent increase in transforming activity.
In support of this model, integration of early-region viral sequences into the host genome has been shown to account for the difference between serum-independent growth and full transformation in BKPyV-infected human embryonic kidney cells.
This integration event could result in positioning of BKPyV TAg coding sequence under the control of nearby cellular promoter-enhancer elements. Findings
Monini et al detected BKPyV in approximately 60% of cancerous and healthy prostates, and the viral load was found to be significantly higher in neoplastic as compared to non-neoplastic tissue. Conclusion
The challenge now is to devise investigative strategies that might lead to conclusive evidence that would allow us to confirm or exclude the role of BKPyV in the development of tumors.
More epidemiological and experimental studies are strongly required.
The possibility of interaction with other host-related factors, infectious agents or environmental components for carcinogenesis warrants more investigation Level of evidence is 5
Human polyomaviruses (HPyV) are small DNA viruses and are widely distributed in human populations. Thirteen distinct HPyVs have been described to date.
Four have been found to show oncogenic potential ( SV40, BKPyV, JCPyV, and MCPyV).
Only strong evidence of the relation of MCPyvV with rare skin cancer (Merkel cell carcinoma).
BK virus:
The primary infection most often occurs in early childhood, with a seroprevalence of 65–90% in 5–9 year old children.
Following primary infection, BKV persists in the kidneys.
BKV genome can be detected in liver, stomach, lungs, parathyroid glands, lymph nodes, brain, peripheral blood mononuclear cells, bladder, uterine cervix, vulva, prostate, lips and tongue.
Upon BKV infection in a permissive host cell (Kidney and salivary gland) , early gene expression leads to DNA replication, followed by late gene expression, production of progeny viral particles and cell death.
In a non-permissive cell, BKV lytic replication is blocked, and abortive infection may result in oncogenic transformation.
Although the oncogenic activity of BKV is well documented in laboratory settings, there is no conclusive evidence of a causal relationship between BKV and cancer in human beings.
Role in carcinogenesis:
The oncogenic role was demonstrated in vivo and in vitro experimental models.
Rodents inoculated with the virus showed that these animals developed tumors at various locations that contained BKV DNA sequences, either integrated into the host genome or in a free episomal form with constitutive TAg expression .
Experimental suggest that while BKV TAg may modulate cellular growth through direct interactions with critical regulatory proteins, additional events (mutations) are required for complete transformation.
Also, they linked the transformation activites to the higher expression of Ha-ras oncogen and inactivation of P53 tumor suppressor gene.
In human:
Various authors have detected BKV genetic material in a wide range of human tumors. For instance, the early BKV genome region has been detected in brain tumors, osteosarcomas, Ewing’s tumors, neuroblastomas and genitourinary tract tissues tumors, including prostatic and bladder cancer.
The contribution of BKV to the etiology of bladder carcinoma in immunocompetent individuals is not well-established. As it was reported in small case series. Some linked it to metastatic UC as tumors expressing BKV- TAg are high grade and invasive.
In prostate cancer, some authors reported significantly higher expression of BKV in malignant cells compared to non-malignant cells. This was denied by others. Based on genetic studies, some postulated that BKV infection implicated suppression of tumor suppressor genes. the TAg inactivates p53 in the atrophic cells, increasing susceptibility to genetic alterations, including tumor suppressor gene mutations that may result in early prostate cancer.
In conclusion, the carcinogenic role of the virus is difficult to demonstrate for many reasons: 1- the viral agent has a high prevalence in the general populations 2- there are a wide range of human tissues in which the virus can be detected 3- The virus has the ability to remain in a latent state for long periods, with occasional reactivations.
Human polyomaviruses are small nonenveloped double-stranded DNA viruses, and about thirteen distinct human polyomaviruses have been described to date. Some of these human polyomaviruses have also been linked with an association with the development of various types of cancer cells in different parts of the human body.
The majority of the infection usually takes place early in life but remains dormant till a state of immunosuppression supervened. The four human polyomaviruses implicated to be oncogenic are; SV40, BKPyV, JCPyV, and MCPyV. BKPyV has been associated with uroepithelia cancer, MCPyV is implicated in some rare skin cancer, and SV40 role in causing cancer is still yet to be substantiated.
The article aims to review the potential role of BKPyV infection in causing cancer
Tropism and epidemiology
BKPyV is a ubiquitous virus affecting about 60 -90% of individuals by age 5-9 years
The effect of the virus on the host is a function of the immune status of the host
BKPyV causes hemorrhagic cystitis and nephropathy (BKAN) in bone marrow and renal transplant patients, respectively
Permissive cells for viral replication are kidney cells such as Vero (African green monkey kidney) RPTE (primary human renal proximal tubule epithelial cells
In a non-permissive cell, BKPyV lytic replication is blocked, and abortive infection may result in oncogenic transformation
Role of BKPyV in carcinogenesis
The mapped two viral oncoproteins are the large T-antigen and the small t-antigen and they induce alteration in normal cell cycle
The most frequently-studied cellular targets of TAg are the p53 family proteins and pRb tumor suppressor protein
The HPyV genome encodes early small-t/large-T antigens, as well as late structural proteins, called VP1, VP2, VP3, and agnoprotein.
The interaction between BKPyV TAg and p53 results in the inactivation of this protein, interfering with the response to DNA damage and inducing the unscheduled onset of the S-phase
Early study has suggested that BKPyv has a tropism for cells in the urinary tract where the virus persists after primary infection
Renal cancer, urothelial bladder cancer, and prostatic cancer have been extensively studied to find any relationship with BKPyv.
Contrasting reports about the role of BKPyV in causing prostate cancer have been published
Conclusion
There is a need for more epidemiological studies to be done to ascertain the relationship between BKPyv and the development of cancer
Introduction and epidemiology
Human polyomavirus is a sdall, double-stranded, non-enveloped DNA viruses . Six viral proteins—two early, one agnoprotein, and three late proteins—are encoded by its genome.
There are more than 13 different forms of polyomaviruses, however only SV40, BKPyV, JCPyV, and MCPyV may be connected to cancer.
With the exception of MCPyV, which has a strong association with the rare skin disease Markel cell carcinoma, the oncogenic potential of polyomaviruses is currently under debate.
Most people acquire BK infection during childhood, typically through feco-oral or vertical transmission; infection affects the uroepithelium and renal tubules, and is lifelong. Seropositivity occurs in 65–90% of people globally by the ages of 5–9 years.
The majority of BK virus infections are asymptomatic, however they can occasionally manifest with hemorrhagic cystitis (often seen in HSCT) or BK nephropathy.
Role in carcinogenesis
In vivo and in vitro research demonstrates the oncogenicity of BKPyV. The big T-antigen (TAg) and the little T are two viral oncoproteins that are encoded in the early region of the BKPyV genome (tAg). These viral products alter cell division, immortilizing, and neoplasticizing cells.
In hamster embryo cells at early passages, a recombinant construct containing the BKPyV TAg gene and the activated c-Ha-ras oncogene also more effectively induced neoplastic transformation than independently transfected genes, suggesting a cooperative effect of the two oncogenes in early carcinogenesis.
Several biological proteins may bind to BKPyV-big TAg, which would impair cell cycle signaling networks. The tumor suppressor proteins p53 and pRb are the targets of TAg.
When BKPyV TAg inactivates p53, it interferes with the DNA damage response and prematurely enters the S-phase.
Early research revealed that BKPyV may cause chronic or latent kidney and urinary tract infections and has a preference for specific cell types. BKPyV may therefore be related to carcinomas in this region. Numerous studies have been conducted on prostatic, urothelial bladder, and renal malignancies.
Recent studies have shown that high-grade cervical squamous intraepithelial lesions include BKPyV DNA together with HPV16.
Conclusion
There is no compelling evidence of a causal connection between BKPyV and human cancer. Therefore, additional research is necessary.The connection between carcinogenesis and other host-related variables must be studied. Level of evidence: narrative review level 5
Human polyomavirus is a small, double stranded, non-enveloped DNA virus. Its genome encodes for 6 viral proteins, 2 early, 1 agnoprotein and 3 late proteins.
More than 13 types of polyomaviruses are present but only 4 types may be linked to malignancy including SV40, BKPyV, JCPyV, and MCPyV
Oncogenic role of polyomaviruses is still debatable except for MCPyV which is strongly linked to Markel cell carcinoma which is a rare skin cancer
BK Infection is usually acquired in childhood, through either feco-oral or vertical transmission, it infects renal tubules and uroepithelium of most of people (around 65–90% of people are infected worldwide by the age of 5-9 years ) and infection remain lifelong
Most of cases of BK virus infection are asymptomatic, it may present with BK nephropathy (graft dysfunction or rarely presents with hemorrhagic cystitis (commonly seen in HSCT
Role of BK virus in carcinogenesis:
The early proteins include large (T) and small tumor antigen (t); the large T antigen is responsible for immortalization of the infected cells and subsequent latent infection.
Detection of BK large T antigens in kidney, bladder and prostate tumors
BK gene was found to be integrated into the cellular genome of urothelial carcinomas in renal transplant recipients
Animals injected with BK virus developed some malignancies at higher frequency such as ependymomas, pancreatic islet tumors, osteosarcomas, fibrosarcomas, liposarcomas, osteosarcomas, nephroblastomas and gliomas
But till now the rule of BK virus in the development of genitourinary malignancies remains debatable and unclear
What is the level of evidence provided by this article?
The oncogenic properties of BKPyV are well demonstrated in in vitro and in vivo experimental models
BKPyV is highly oncogenic in rodents
developed tumors at various locations that contained BKPyV DNA sequences, either integrated into the host genome or in a free episomal form with constitutive TAg expression
. In addition, animals injected with BKPyV frequently developed ependymomas, pancreatic islet tumors, osteosarcomas,fibrosarcomas, liposarcomas, osteosarcomas, nephroblastomas and gliomas
Transgenic mice expressing the BKPyV early genome region were found to develop highly tissue-specific tumors. Small et al. showed that these animals developed primary hepatocellular carcinomas and renal tumors
studies showing that human embryonic kidney cells persistently infected with BKPyV exhibited a semi-transformed phenotype and that full transformation resulted from the additional presence of activated Ha-ras oncogenes Therefore, p53 inactivation by BK TAg may lead to random mutational events that could activate cellular oncogenes or inactivate other tumor suppressor genes.
In some cases, BKPyV may not be directly involved in the development of cancer, but instead, play a role as a co-factor in the carcinogenic process. For instance, the virus may co-infect cells that were previously infected by another oncogenic virus, increasing susceptibility to cancer. In fact, HPyVs have been detected in various tissues that are susceptible to transformation by HTLV-I, HCV, HPV, EBV, HHV-8 and HBV
recent reports have documented the presence of BKPyV DNA in association with HPV16 in high-grade cervical squamous intraepithelial lesions .
. Early findings established that BKPyV has a tropism for certain cell types and that this agent can establish a persistent or latent infection in the kidney and urinary tract . Therefore, carcinomas that affect this anatomical zone are likely candidates for associations with BKPyV. Among these diseases, renal cancer, urothelial bladder cancer, and prostatic cancer have been extensively studied
BKPyV & bladder carcinoma in immunocompetent individuals
Some studies demonstrate BKPyV DNA sequences at high frequencies in bladder carcinoma However, these studies were small case series that either lacked a control group or relied entirely on antibody seroprevalence
In a multi-center study, Polesel et al. found similar a prevalence of the viral DNA in a group of 114 transitional bladder carcinoma cases and a group of 140 hospital controls. This result does not support the role of BKPyV in bladder cancer among immunocompetent individuals
In a retrospective study, Roberts et al. reported that while no positive BKPyV TAg urothelial carcinomas were found in a series of non-transplanted patients (0/20), strong nuclear staining for TAg was seen in the urothelial carcinoma of one renal transplant patient This data indicates that although associations between BKPyV and these tumors are rare, the virus may have a tumorigenic role in some cases.
Prostate cancer
Das and Russo found in PCa cases, lower prevalence in controls
. Lau et al., using in situ, detected BKPyV in only 2/30 prostatic adenocarcinomas, and no TAg expression was detected in neoplastic tissue
Sfanos et al. of 338 analyzed total samples from 200 patients for BKPyV DNA and detected only one positive sample
In Chile, our group found only 6/69 (8.7%) BKPyV DNA-positive prostate carcinomas, and the TAg transcripts were detected in 2/6 (33%) of BKPyV positive cases
a retrospective review of kidney transplant patients Chen et al. reported that 6/864 patients developed polyomavirus-associated nephropathy (PVAN). Malignancy occurred in 5/6 PVAN patients, finding suggests that the possible oncogenic mechanism involves deregulation of the proliferation inducer TAg
Level III Evidence– studies with essentially minimal design, ‘descriptive’ and lowest level of evidence
Background
-Human polyomaviruses (HPyVs) are small, nonenveloped, double-stranded DNA viruses belong to the polyomaviridae family.
-The HPyV genome encodes early coding region, late coding region and non-coding control region NCCR.
-Around 14 HPyVs discovered. Four viruses have been found to show oncogenic potential — SV40, BKPyV, JCPyV, and MCPyV.
-Skin cancer and Merkel cell carcinoma are strong linked to MCPyV.
BK virus Viral entry
Various proteins are involved in various functions related to the HPyV life cycle, such as regulating viral gene expression or inducing viral maturation and replication.
Tropism and epidemiology
-HPyV infection typically occurs early in life as primary infection with prevalence 65-90% , and persists throughout the lifespan.
-In immunocompromised individuals, virus reactivation cause significant morbidities e.g; hemorrhagic cystitis and BKAN in HSCT and KTRs.
– Once the virus enters to the body, transport to different permissive host cell kidney and salivary gland.
– In a non-permissive cell, BKPyV lytic replication is blocked, and abortive infection may result in oncogenic transformation.
– There is no conclusive evidence of a causal relationship between BKPyV and cancer in human beings.
Role in carcinogenesis *Tumors developed in vivo models
-The transforming ability of BKPyV is well documented in experimental animal models. Animals injected with BKPyV frequently developed cancer.
*Transforming properties in vitro models * BKPyV alterations occur before immortalization
-The early region of genome, which encodes two oncoproteins the large TAg & small T-antigen (tAg) induce alterations in the normal cell cycle, leading to cell immortalization and neoplastic transformation.
– TAg interact with p53 results in its inactivation, interfering with the response to DNA damage and inducing onset of the S-phase.
– TAg interact with pRb leads to the release and nuclear translocation of the E2 factor and inducing quiescent cells to enter the S-phase.
-tAg inhibiting protein phosphatase 2A (PP2A), an essential tumor suppressor in numerous death-signaling pathways.
-TAg binds to or inactivates tumor suppressor proteins, with a second step leading to cellular oncogene activation.
-TAg induces chromosomal instability in human embryonic fibroblasts, these alterations occur before immortalization.
* Viral oncogenes are expressed in tumors
* BKPyV genome detected in human tumors
– HPyVs play a role as a co-factor in the carcinogenic process. It has been detected in various tissues that are susceptible to transformation by HTLV-I, HCV, HPV, EBV, HHV-8 and HBV.
-Some studies demonstrate BKPyV DNA sequences at high frequencies in bladder carcinoma and prostate Ca.
– “hit-and run” carcinogenesis mechanism, the loss of BKPyV in the tumor cells could be due to selection against TAg by the immune system, dilution of viral episomes due to lack of replication or pro-apoptotic effects mediated
Evidence for a non-carcinogenic role:
– Poor and not efficient transforming activity in human cells
– Ubiquitous distribution in normal human cells and tissues
– Variable BKPyV presence in tumors among different studies
Conclusion
There is no conclusive evidence of a causal relationship between BKPyV and cancer in human beings. Therefore, more studies are required.
The interaction with other host-related factors for carcinogenesis need to be investigated.
HPyVs are tiny, nonenveloped, double-stranded DNA viruses having icosahedral symmetry. They’re polyomaviridae. HPyV encodes early small- and large-T antigens and the late structural proteins VP1, VP2, VP3, and agnoprotein. Large T and small t antigen genes and the splice variants T = 135, T = 136, and T = 165 are transcribed before DNA replication. DNA replication transcribes the late region. 72 VP1 pentamers interact with VP2/VP3 molecules in the HPyV capsid. These viruses produce two mature miRNAs from a pre-miRNA.
-HPyVs produce productive infections in native hosts but latency and possible genome integration in heterologous, non-permissive hosts. Early fecal-oral transmission of HPyV leads to lifelong infection. Fourteen HPyVs have been found in the previous several years using high-throughput sequencing methods.
BK entry:
VP1 attaches cells to BKPyV through α2, 8-SA-containing b-series gangliosides (GD1b/GT1b). VP1 forms a crystal-like combination with GD3, a disialic acid ganglioside, and two sialic molecules. Site-directed mutagenesis tested this model. The terminal sialic acid residue of GD3 must touch VP1 for viral infection.
Tropism and epidemiology:
Strict anthroponosis BKPyV is widespread. The seroprevalence is 65–90% in 5–9-year-olds, indicating early infection. Kidneys harbor BKPyV after initial infection. When immunosuppressed, the virus causes considerable morbidity. In bone marrow and kidney transplant patients, BKPyV induces hemorrhagic cystitis and BKAN.
The transmission route is unknown, although BKPyV’s great resistance to environmental inactivation and large quantities in human sewage and other water sources imply fecal-oral transmission. Since salivary glands and oropharyngeal cells do not survive BKPyV, the digestive system may be critical for viral transmission.
Carcinogenesis:
In vitro and in vivo experiments show that BKPyV is oncogenic. The early portion of the BKPyV genome encodes two viral oncoproteins, the big T-antigen (TAg) and the small T. (tAg). These viral products affect the cell cycle, immortalizing, and neo-plasticizing cells.
A recombinant construct containing the BKPyV TAg gene and the activated c-Ha-ras oncogene also induced neoplastic transformation at early passages in hamster embryo cells more efficiently than independently transfected genes, suggesting a cooperative effect of the two oncogenes in early carcinogenesis.
BKPyV-big TAg may bind several cellular proteins and disrupt cell cycle signaling pathways. TAg targets the p53 and pRb tumor suppressor proteins.
BKPyV TAg inactivates p53, disrupting the DNA damage response and triggering the S-phase prematurely.
Early studies showed that BKPyV has a tropism for particular cell types and may cause chronic or latent kidney and urinary tract infections. Thus, BKPyV may be linked to carcinomas in this area. Renal, urothelial bladder, and prostatic cancers have been widely investigated.
Evidence of BKPyV carcinogenicity:
–Viral oncogenes are expressed in tumors
-Tumors developed in vivo models
-Transforming properties in vitro models
-BKPyV alterations occur before immortalization
-BKPyV genome detected in human tumors
Evidence for a non-carcinogenic role:
–Poor and not efficient transforming activity in human cells
-Ubiquitous distribution in normal human cells and tissues
-Variable BKPyV presence in tumors among different studies
Conclusion :
Now we need to find ways to prove or disprove BKPyV’s participation in tumor formation. Epidemiological and experimental investigations are needed. Carcinogenesis may involve host-related factors, infectious pathogens, or environmental variables.
What is the level of evidence provided by this article?
Human poyloma virus(HPyV) are member of polyomaviridae family, small, icosahedral , DNA viruses.
The genome (5000 base pairs) encodes 3 regions; early coding( large T and small t antigen),non coding and late coding region(regulate gene expression)
Four polyomaviruses may have oncogenic potential e.g SV40, BKPyV, JCPyV , and MCPyV in rare skin cancer and Markel cell carcinoma.
Epidemiology:
Primary infection occur in 65 to 90% in the first few years of life 5 to 9 years
Transmission may be feco-oral, vertical or transplacental
At the moment , there is no conclusive evidence of a causal relationship between BKPyV and cancer in human (the presence of BKPyV may not necessarily indicate their involvement in the neoplastic process).
Role in carcinogenesis:
Large T antigen and small t antigen are associated with cellular alterations and neoplastic transformation.
Animals injected with BKVyV developed ependymomas, pancreatic islet cell tumors, osteosarcoma and other tumors.
Mutations may be required for the process of carcinogenesis
Integration of the viral sequences into host genome
Inactivation of tumor suppressor proteins
Chromosomal alterations and instability
Co-factor in the carcinogenesis , not directly involved
Association with bladder & prostate cancer.
“Hit-and-run” carcinogenesis mechanism
Conclusion:
At the moment , there is no conclusive evidence of a causal relationship between BKPyV and cancer in human. Therefore, more epidemiological and experimental studies badly needed to figure out this relationship.
2.What is the level of evidence provided by this article?
Background
BKV is a double-stranded DNA viruses with 5000-bp genome.
It consists of 3 regions including
-the early region, that is transcribed before DNA replication ,composed of large T and small t antigen genes and the splice variants T = 135, T = 136,and T = 165 .
-The late region is transcribed concomitant with DNA replication
-A non-coding control region (NCCR) is located between the oppositely-oriented transcriptional units that encode for early and late transcripts.
In natural hosts, BKV causes a productive infection, and in non-permissive hosts, the virus is latent with potential integration into the host genome.
BKV infection occurs early in life and persists throughout the lifespan.
There are 14 Human polyomavirus types detected and their association with cancer is studied .
Particularly MCPyV appears to have a role in a rare skin cancer, Merkel cell carcinoma also SV40 seems to have a carcinogenic role but is still controversial. BK virus Viral entry
A specific contact between the terminal sialic acid residue of GD3 and VP1 is needed for virus infection.
BKPyV entry is caveolin- and clathrin-independent, BKPyV utilizes an uncharacterized endocytic pathway.
When the virus enters the cell to start replication retrograde transit of endocytic vesicles to the endoplasmic reticulum occurs , then partial disassembly occurs.
The virus enters the nucleus via the importin-α/β pathway. Tropism
The primary infection usually occurs early in life and the virus remains latent then if the host becomes immunocompromised the virus is activated .
BKPyV causes hemorrhagic cystitis in bone marrow transplants and nephropathy in renal transplant cases.
Feco oral route ,vertical transmission are infection methods
Once BKPyV infect a permissive host cell, early gene expression leads to DNA replication,late gene expression and cell death.
Kidney and salivary gland cells are permissive for the BKV infection.
In non-permissive cells, BKPyV abortive infection can have oncogenic transformation.
Till now the causative relation of BKPyV to cancer is unconclusive Carcinogenic role
BKPyV carcinogenic effects are detected in vitro and in vivo experimental models but this oncogenic effect is not always detcetd in humans .
The early region of the BKPyV genome harbours the transformation ability leading to cell immortalization and carcinogenesis .
BKPyV large TAg is a multifunctional protein which bind various cellular proteins, changing signaling pathways and it targets p53 family proteins and pRb tumor suppressor proteins.
A difference between SV40 and BKPyV TAg activity was notice and could be attributed to lower expression levels of the BKPyV promoter and enhancer elements.
Another model caould be that the role of BKPyV TAg in oncogenesis involves BKPyV Tag binding to or inactivates tumor suppressor proteins as p53 ,then leading to cellular oncogene activation.
It was declared by some studies that BKPyV genetic material was detected in multiple human tumors as brain and Ewing tumors ,on the contrary this was denied by other studies.
BKPyV can have an indirect role in carcinogenesis acting as a cofactor as there was an association between BKPyV and precancerous cervical lesions.
More studies are needed to clarify if a certain transformation mechanism involving BKPyV and HPV occurs in cervical cancer.
BKPyV has a tropism for some cell types establishing persistent or latent infection in the kidney and urinary tract leading to renal cancer, bladder cancer, and prostatic cancer.
Another study concluded that polyomavirus-associated nephropathy (PVAN) can increase malignancy risk.
The possible oncogenic mechanism is deregulation of the proliferation inducer Tag.
BKPyV codes a miRNA which can be complementary to Tag coding mRNA.
Studies are assessing if these miRNAs are functional during BKPyV infection and if it has a role in BKPyV induced transformation.
Data on the role of BKPyV in cancer prostate is contradictory.
A possible tumorigenic mechanism was suggested where TAg inactivates p53 in the atrophic cells , leading to tumor suppressor gene mutations that may result in early prostate cancer. Conclusion
More studies are needed to evaluate the BKV role in tumorigenesis either confirm or deny .
-level of evidence is V
Human polyoma virus are DNA virus. Genome encodes small t/ Large T antigens, late structural proteins called VP1, VP2, VP3 and agnoprotein.
VP1 binds to GD3 of cell – endosome – endocytic vesicles -ER – partial dissassembly- Viral particle escape to the cytoplasm – hijacking ER proteins – virus enters the nucleus.
Role in carcinogenesis
genome encodes 2 viral oncoproteins – Tantigen large and small t antigen – induce alteration in normal cell cycle – leads to cell immortalisation and neoplastic transformation
BkV Tag protein interacts with p53 and inhibits it ,thus interfering response to DNA damage, inducing unscheduled onset of the S phase – accumulation of genetic alterations .
BKV Tag also interacts with pRb – nuclear translocation of E2 factor – genes expressed – induce quiscent cells to enter Sphase.
tAg inhibits PP2 A a tumour suppressor gene – promotes cell proliferation via MAPK.
In addition mutation or alteration of viral promoter enhanced elements leading to Increased expression of early genes with a increase in transforming activity.
Alternative model – BKV Tag binds to or inactivate tumour suppressor proteins P53 with as a second step leading to cellular oncogene activation Ha-ras.
BKX Tag induces chromosomal instability.
BKV genome has been detected in brain tumours,Osteosarcomas, Ewing’s tumour,neuroblastomas, genitourinary tract tissue tumours.
In some cancers Bay genome may play role as a cofactor.
HPyVs may act as a cofactor to H TLV-1, HCV,HPV, E BV,HHV-8 and HBV.
HPyVs along with H PV-16 is seen in precancerous cervical cells.
BKPyV is linked to metastatic bladder Carcinoma in immunosuppressed transplant recepient.
BKPyV constitutes an important factor for early prostrate tumorigenesis.
Evidence for BKPyV Carcinogenicity Viral oncogenes are expressed in tumours. BKPyV alteration occur before immortalisation BKPyV genome detected in human tumour. Tumours developed in vivo models.
The oncogenic properties of BKPyV are well-demonstrated in in vitro and in vivo experimental models. The transforming activity has been mapped in the early region of the BKPy genome, which encodes two viral oncoproteins: the large T-antigen (TAg) and the small t-antigen (tAg). These viral products induce alterations in the normal cell cycle, ultimately leading to cell immortalization and neoplastic transformation.
n 2012, the International Agency for Research on Cancer (IARC) evaluated the carcinogenicity of the BK virus (BKPyV), reporting that BKPyV is “possibly carcinogenic to humans
Conclusions:we need more RCTs to ensure carcinogenicity of BKV
Level of evidence:5
This review explores the BKPyV infection from a historical point of view, including biological aspects related to viral entry, tropism, epidemiology and mechanisms potentially involved in BKPyV-mediated human carcinogenesis.
Human polyomaviruses (HPyV), are small DNA viruses classified into the polyomaviridae family.
Thirteen distinct HPyVs have been described to date. Some of these viruses have been found in human tumors, suggesting an etiological relationship with cancer.
There is convincing evidence of an oncogenic role for the Merkel cell polyomavirus (MCPyV). This HPyV has been linked to rare skin cancer, Merkel cell carcinoma (MCC).
In 2012, the International Agency for Research on Cancer (IARC) evaluated the carcinogenicity of the BK virus (BKPyV), reporting that BKPyV is “possibly carcinogenic to humans.”
The primary infection most often occurs in early
childhood, with a seroprevalence of 65–90% in 5–9 year old
children . After the primary infection, BKPyV persists in the kidneys.
In immunosuppressed patients, BKPyV causes hemorrhagic cystitis in bone marrow transplant and nephropathy (BKAN) in renal transplant
patients .
BKPyV genomes also detected in a wide spectrum of normal tissues including liver, stomach, lungs, parathyroid glands, lymph nodes, brain, peripheral blood mononuclear cells, bladder, uterine cervix, vulva, prostate, lips and tongue .
The oncogenic properties of BKPyV are well demonstrated
in in vitro and in vivo experimental models. The transforming activity has been mapped in the early region of the BKPyV genome, which encodes two viral oncoproteins: the large T-antigen (TAg) and
the small t-antigen (tAg). These viral products induce alterations
in the normal cell cycle, ultimately leading to cell immortalization and neoplastic transformation .
Various authors have detected BKPyV genetic material in a wide range of human tumors . The early BKPyV genome region has been detected in brain tumors, osteosarcomas, Ewing’s tumors, neuroblastomas and genitourinary tract tissues tumors, including prostatic and bladder cancer . In contrast, other authors reported no association between
BKPyV DNA and tumors .
Here some comparison points for carcinogenicity role of BKPYV:
Evidences of BKPyV carcinogenicity:
1- Viral oncogenes are expressed in tumors
2- Tumors developed in in vivo models
3- Transforming properties in vitro models
4- BKPyV alterations occur before immortalization
BKPyV genome detected in human tumors
Evidences for a non-carcinogenic role:
1- Poor and not efficient transforming activity in human cells
2- Ubiquitous distribution in normal human cells and tissues
3- Variable BKPyV presence in tumors among different studies
In conclusion, it is required now is to advise for more epidemiological and experimental studies . In addition, the possibility of interaction with other host-related factors,
infectious agents or environmental components for carcinogenesis warrants more investigation
level 5
This article is level evidence 5
BK virus belong to DNA virus group
Risk factors and pathogenesis: The risk factors include
· Factors related to recipient includes: high immunological risk like (HLA incompatibility, ABO incompatibility, and use of antilymphocyte antibodies) which reflect on degree of immunosuppression, diabetes mellitus, rejection episodes, older age, steroid use cytomegalovirus co-infection.
· Factors related donor: seropositive renal donor, viruria in the donor.
Level of evidence 5
-Human polyoma viruses are small double stranded DNA viruses with 4 being linked to oncogenicity Merkel cell polyoma virus, SV40, BK virus and JC virus.
– BKV has been isolated from:
-Urogenital malignancies
-brain tumors
-osteosarcomas
-Ewings tumors
But presence of BKV DNA doesn’t essentially possess a neoplastic involvement of the virus.
-More studies are needed to show evidence of oncogenesis by BKV infection.
Summary
Introduction
This article is surrounding the role of BK virus in cancer. BK virus is a small DNA virus that belongs to the polyomavirdiae family. It is possible that this virus has an etiological link with cancer. In particular, Merkel cell polyomavirus is linked with a skin cancer called Merkel cell carcinoma.
This article looks at BKV in a wholesome manner, from, biology, entry, epidemiology to mechanisms involved in human carcinogenesis.
Discussion
BKV infection is a primary infection that occurs in early childhood, generally between the ages of 5-9 years. Following primary infection, BKV remains in the kidneys, and causes significant morbidity especially in immunocompromised patients. Complications in the immunocompromised population may include hemorrhagic cystitis and nephropathy.
Transmission can occur through the feco-oral route. Vertical transmission can also occur from mother to fetus.
Viral products of BKV genome induce alterations normal cell cycle of the host, leading to cell immortalization and neoplastic transformation. Transforming ability of BKV depends on its two oncoprotiens – large T antigen (TAg) and small T antigen (tAg). TAg, the larger protein, is highly multifunctional and can bind to several cellular proteins, changing signaling pathways that are involved in cell control. p53 and pRb tumor suppressor proteins are some important proteins that are bound by TAg. This interaction leads to DNA damage and unscheduled onset of S phase.
Conclusion
Further studies are needed to understand the etiology of BKV in cancer and also to mitigate treatment strategies that would prevent or restore DNA damage caused by BKV. In order to achieve this, more environmental and epidemiological studies are necessary.
Another aspect to investigate regarding this topic would be interaction of the virus with host associated factors, infectious agents, and environmental components.
Level of evidence
This is a narrative review, thus level of evidence is 5.
Introduction:
Human polyomaviruses (HPyV) belong to the polyomaviridae family and are small, icosahedral DNA viruses. The HPyV genome, consisting of approximately 5000 base pairs, encodes three regions: the early coding region (large T and small t antigen), non-coding region, and late coding region (involved in gene regulation). Among the polyomaviruses, SV40, BKPyV, JCPyV, and MCPyV have been implicated in oncogenic potential, particularly in rare skin cancer and Merkel cell carcinoma.
Epidemiology:
Primary infections with HPyV commonly occur in early childhood, with a seroprevalence ranging from 65% to 90% in children aged 5 to 9 years. Transmission of the virus can occur through fecal-oral route, vertical transmission, or transplacental transmission. Currently, there is no conclusive evidence establishing a causal relationship between BKPyV and cancer in humans, as the presence of BKPyV in the body may not necessarily indicate its involvement in the neoplastic process.
Role in Carcinogenesis:
The large T antigen and small t antigen encoded by BKPyV have been associated with cellular alterations and neoplastic transformation. Animals injected with BKPyV have developed various tumors such as ependymomas, pancreatic islet cell tumors, osteosarcomas, and others. The process of carcinogenesis may involve mutations, integration of viral sequences into the host genome, inactivation of tumor suppressor proteins, chromosomal alterations and instability, and potential co-factors in carcinogenesis. BKPyV has also been associated with bladder and prostate cancer, but the exact mechanisms remain unclear. The “hit-and-run” carcinogenesis mechanism has been proposed, where the virus may play a role in initiating the process but is not directly involved in the development of cancer.
Conclusion:
Currently, there is no conclusive evidence establishing a causal relationship between BKPyV and cancer in humans. Therefore, further epidemiological and experimental studies are urgently needed to elucidate this relationship and provide more concrete evidence.
Level of Evidence:
The level of evidence provided by this article is Level V.
The aim of this study was to investigate the molecular mechanisms underlying human polyomaviruses (BKPyV) infection and its potential association with malignancy.
Introduction:
Human polyomaviruses (HPyVs) belong to the polyomaviridae family and are small, non-enveloped, double-stranded DNA viruses. The HPyV genome encodes early antigens, small-t/large-T antigens, and late structural proteins such as VP1, VP2, VP3, and agnoprotein. HPyVs can establish a productive infection in their natural hosts, while in non-permissive hosts, they can establish latency and potentially integrate into the host genome. Among the 14 described HPyVs, four polyomaviruses (SV40, BKPyV, JCPyV, and MCPyV) have shown oncogenic potential, with MCPyV being strongly associated with cancer. The potential carcinogenic role of SV40 remains controversial.
Role in Carcinogenesis:
The oncogenic properties of BKPyV have been demonstrated in vitro and in vivo experimental models. BKPyV encodes two viral oncoproteins, large T-antigen and small t-antigen, which can induce alterations in the normal cell cycle and result in neoplastic transformation. BKPyV large T-antigen interacts with cellular proteins, affecting signaling pathways involved in cell cycle control. Animals injected with BKPyV frequently develop various types of tumors. However, while BKPyV’s transforming ability is well-documented in experimental rodent models, definitive evidence of its transforming activity in humans and primates is inconsistent.
Evidence of BKPyV Carcinogenicity:
Several lines of evidence support the potential carcinogenicity of BKPyV, including the expression of viral oncogenes in tumors, tumor development in in vivo models, and the transforming properties observed in in vitro models. Additionally, BKPyV alterations have been detected before immortalization, and BKPyV genomes have been found in human tumors.
Evidence for a Non-Carcinogenic Role:
On the other hand, there is evidence suggesting a non-carcinogenic role for BKPyV. Its transforming activity in human cells is less efficient compared to experimental models, and the virus is ubiquitously distributed in normal human cells and tissues. The presence of BKPyV in tumors varies among different studies.
Conclusion:
Conclusive evidence is necessary to confirm or exclude the role of BKPyV in tumor development. Further epidemiological and experimental studies are required to shed more light on this topic. The possibility of interactions between BKPyV and other host-related factors, infectious agents, or environmental components in carcinogenesis warrants further investigation.
Level of Evidence:
The level of evidence provided by this article is Level V.
Abstract:
DNA viruses classified into the Polyomaviridae family, are widely distributed in human populations.
Thirteen distinct HPyVs have been described to date. Some of these viruses have been found in human tumors, suggesting an etiological relationship with cancer
. In particular, convincing evidence of an oncogenic role has emerged for a specific HPyV, the Merkel cell polyomavirus (MCPyV). This HPyV has been linked to rare skin cancer, Merkel cell carcinoma (MCC).
In 2012, the International Agency for Research on Cancer (IARC) evaluated the carcinogenicity of the BK virus (BKPyV), reporting that BKPyV is “possibly carcinogenic to humans.
Background:
HPyVs are small, nonenveloped, double-stranded DNA viruses.
Polyomaviridae family.
The HPyV genome encodes early small-t/large-T antigens as well as late structural proteins called VP1, VP2, VP3, and agnoprotein.
The early region, is composed of large T and small t antigen genes and the splice variants T = 135, T = 136, and T = 165. HPyV capsid harbors 72 pentamer of VP1, which interacts with the VP2/VP3 molecules associated with each pentamer.
These viruses encode a pre-miRNA for generation of two mature miRNAs, a non-coding control region (NCCR).
A non-coding control region (NCCR) is located between the oppositely-oriented transcriptional units that encode for early and late transcripts. The NCCR contains the promoters and enhancers for regulation of gene expression and harbors the replication origin.
Agnoprotein is expressed from the 5’region of VP2 open reading frame. It is believed that this protein is involved in various functions related to the HPyV life cycle, such as regulating viral gene expression or inducing viral maturation.
Fourteen HPyVs have been described, most of which were discovered in the last few years.
Four polyomaviruses have been found to show oncogenic potential — SV40, BKPyV, JCPyV, and MCPyV — although there is strong evidence of such a link only in the case of MCPyV. This virus appears to play a role in a rare skin cancer, Merkel cell carcinoma.
Entry of Virus:
Contact between the terminal sialic acid residue of GD3 and VP1 is essential for virus infection.
BKPyV entry is caveolin- and clathrin-independent.
Enter nucleus via the importin-α/β pathway, guided by nuclear localization signals present in the minor capsid proteins VP2 and VP3.
Tropism and epidemiology:
The primary infection:
Most often occurs in early childhood, with a Seroprevalence of 65–90% in 5–9 year-old children .Following primary infection, BKPyV persists in the kidneys.
If the host becomes immunosuppressed, the virus causes significant morbid.
BKPyV causes hemorrhagic cystitis and nephropathy (BKAN).
Transmission mechanism:
Most likely fecal-oral, Tran’s placental transmission is suggested.
Infection in a permissive host cell, early gene expression leads to DNA replication, followed by late gene expression, production of progeny viral particles and cell death.
A non-permissive cell, BKPyV lytic replication is blocked, and abortive infection may result in oncogenic transformation.
There is no conclusive evidence of a causal relationship between BKPyV and cancer in human beings.
Role in carcinogenesis:
The oncogenic properties of BKPyV are well demonstrated in in vitro and in vivo
TAg are the p53 family proteins and pRb tumor suppressor proteins. The interaction between BKPyV TAg and p53 results in the inactivation of this protein, interfering with the response to DNA damage and inducing the unscheduled onset of the S-phase. Addition, the interaction between BKPyV TAg and pRb leads to the release and nuclear translocation of the E2 factor (E2F) family of transcription factors and subsequent expression of genes, inducing quiescent cells to enter the S-phase.
Animal injected with BKPyV frequently developed ependymomas, pancreatic islet tumors, osteosarcomas, fibro sarcomas, liposarcomas, osteosarcomas, nephroblastomas and gliomas. Primary hepatocellular carcinomas and renal tumors.
Although the transforming ability of BKPyV is well documented in experimental rodent models, definitive transforming activity is not always observed in human and primate.
Conclusion:
The challenge now is to devise investigative strategies that might lead to conclusive evidence that would allow us to confirm or exclude the role of BKPyV in the development of tumor.
Level of evidence V.
Abstract:
Human polyomaviruses are DNA viruses belong to polyomaviridae family,
There are 13 types of virus Some of these viruses have been found in human tumors, suggesting an etiological relationship with cancer.
convincing evidence of an oncogenic role has emerged for a specific HPyV, the Merkel cell polyomavirus (MCPyV).
This HPyV has been linked to rare skin cancer, Merkel cell carcinoma (MCC).
In 2012, (IARC) reporting that BKPyV is “possibly carcinogenic to humans.”
Background:
Human polyomavirus is virus. Infection started early in life and become dormant .the infection route is through fecooral root and may also with trans placental transmission .
Four polyomaviruses have been found to be carcinogenic — SV40, BKPyV, JCPyV, and MCPyV — which is linked to Merkel cell carcinoma
Tropism and epidemiology:
The primary infection is acquired in early childhood, with a sero-prevalence of 65–90% in 5–9 year old children..
Post primary infection, BKPyV it persists dormant in the kidneys.
In immune-incompetent state , the virus reactivate and cause nephropathy (BKAN) in renal transplant patients.
BKPyV genomes have also been detected in liver, stomach, lungs, parathyroid glands, brain, bladder, uterine cervix and prostate.
Role of BKPV in carcinogenesis:
1) Viral oncogenes are expressed in tumors.
2) Tumors developed in in vivo models.
3) Transforming properties in in vitro models
4) BKPyV alterations occur before immortalization
5) BKPyV genome detected in human tumors
Conclusion:
The challenge now is to devise investigative strategies that might lead to conclusive evidence that would allow us to confirm or exclude the role of BKPyV in the development of tumors. Thus, more epidemiological and experimental studies are strongly required.
Level of evidence is 5
In 2012, the International Agency for Research on Cancer (IARC) evaluated the carcinogenicity of the BK virus (BKPyV), reporting that BKPyV is “possibly carcinogenic to humans.” This review explores the BKPyV infection from a historical point of view, including biological aspects related to viral entry, tropism, epidemiology and mechanisms potentially involved in BKPyV-mediated human carcinogenesis.
Evidences of BKPyV carcinogenicity–
Viral oncogenes are expressed in tumors.
Tumors developed in in vivo models.
Transforming properties in in vitro models
BKPyV alterations occur before immortalization
BKPyV genome detected in human tumors
Evidences for a non-carcinogenic role-
Poor and not efficient transforming activity in human cells.
Ubiquitous distribution in normal human cells and tissues.
Variable BKPyV presence in tumors among different studies
Conclusion- The challenge now is to devise investigative strategies that might lead to conclusive evidence that would allow us to confirm or exclude the role of BKPyV in the development of tumors. Thus, more epidemiological and experimental studies are strongly required
Level of Evidence-5
Abstract
Human polyomaviruses (HPyV), are DNA viruses belong to polyomaviridae family, it common .
Thee is 30 types of virus . Some of these viruses have been found in human tumors, suggesting an etiological relationship with cancer.
convincing evidence of an oncogenic role has emerged for a specific HPyV, the Merkel cell polyomavirus (MCPyV).
This HPyV has been linked to rare skin cancer, Merkel cell carcinoma (MCC).
In 2012, (IARC) reporting that BKPyV is “possibly carcinogenic to humans.”
Background:
Human polyomaviruses is virus. Infection started early in life and become dormant . the infection route is through feco oral root and may also with trans placental transmission .
Four polyomaviruses have been found to be carcinogenic — SV40, BKPyV, JCPyV, and MCPyV — which is linked to Merkel cell carcinoma
Tropism and epidemiology:
The primary infection is acquired in early childhood, with a sero-prevalence of 65–90% in 5–9 year old children.
Post primary infection, BKPyV it persists dormant in the kidneys.
In immune-incompetent state , the virus reactivate and cause nephropathy (BKAN) in renal transplant patients.
BKPyV genomes have also been detected in liver, stomach, lungs, parathyroid glands, brain, bladder, uterine cervix and prostate .
Permissive cells for viral replication are kidney cells, primary human renal proximal tubule epithelial cells and some salivary glands cells.
In a non-permissive cell, BKPyV replication is blocked, and abortive infection may result in oncogenic transformation.
The oncogenic activity of BKPyV is well documented at vitro but there is no conclusive link to cancer.
Role of BKPV in carcinogenesis:
– The transforming activity has been mapped in the early region of the BKPV genome, which encodes two viral oncoproteins: Tag and tAg.
– BKPV is highly oncogenic in rodents.
– Conclusive transforming activity of virus is not always conclusive.
– BKPV genetic material is found in wide range of human tumors: brain tumors, osteosarcomas, Ewing’s tumors, neuroblastomas, prostatic, & bladder cancer. But this is not approve for a causative link.
– BKPV may present as co-infection in cells infected by another oncogenic virus (HTLV-I, HCV, HPV, EBV, HHV-8 & HBV).
– Monini et al. found BKPV in about 60% of healthy prostates and prostatic cancer. .
Conclusion
– The challenge now is to devise investigative strategies that might lead to conclusive evidence that would allow us to confirm or exclude the role of BKPyV in the development of tumors.
– Thus, more epidemiological and experimental studies are strongly required.
– the possibility of interaction with other host-related factors, infectious agents or environmental components for carcinogenesis warrants more investigation.
Q2- Level of evidence: 5
Background
Human polyomaviruses (HPyVs) are small, nonenveloped, double-stranded DNA viruses belong to the polyomaviridae family.
-The HPyV genome encodes early coding region, late coding region and non-coding control region NCCR.
-Around 14 HPyVs discovered. Four viruses have been found to show oncogenic potential — SV40, BKPyV, JCPyV, and MCPyV.
-Skin cancer and Merkel cell carcinoma are strong linked to MCPyV.
Viral entry
virus gains entry into the cell thereafter it reaches to the nucleus for replication, once in the endoplasmic reticulum, partial disassembly occurs and the viral particles escape to the cytoplasm finally entering the nucleus
Tropism & epidemiology
Strict anthroponosis BKPyV is widespread. The seroprevalence is 65–90% in 5–9-year-olds, indicating early infection. Kidneys harbor BKPyV after initial infection. When immunosuppressed, the virus causes considerable morbidity. In bone marrow and kidney transplant patients, BKPyV induces hemorrhagic cystitis and BKAN.
The transmission route is unknown, although BKPyV’s great resistance to environmental inactivation and large quantities in human sewage and other water sources imply fecal-oral transmission. Since salivary glands and oropharyngeal cells do not survive BKPyV, the digestive system may be critical for viral transmission.
Role in carcinigenesis
The oncogenic properties of BKPyV are welldemonstrated in in vitro and in vivo
Two viral oncoproteins: the large T-antigen (TAg) and the small t-antigen (tAg)
The interaction between BKPyV TAg and p53 results in the inactivation of this protein, interfering with the response to DNA damage and inducing the unscheduled onset of the S-phase
Transforming ability of BKPyV is welldocumented in experimental rodent models, definitive transforming activity is not always observed in human
Inactivation of tumour suppressor gene has a role .
Alteration in chromosomal activity
Main association with bladder and prostate cancer.
Conclusion
Need conclusive evidence to confirm the association and exclusion of BKVPyL with carcinomas.
Interaction of infectious agents and environmental components in carcinogenesis.
Level V
Role of BK human polyomavirus in cancer:
Summarise this article:
Background:
– Human polyomaviruses (HPyV) are small DNA viruses belonging to the polyomaviridae family
– 13 distinct HPyVs have been described so far, with some being found in tumors
– HPyV infection occurs early in life through fecal-oral transmission
– 4 polyomaviruses have been found to have oncogenic potential i.e., SV40, BKPyV, JCPyV and MCPyV
– strong evidence only exists for MCPyV which is associated with merkel cell carcinoma, a rare skin cancer
BK virus viral entry
– virus gains entry into the cell thereafter it reaches to the nucleus for replication, once in the endoplasmic reticulum, partial disassembly occurs and the viral particles escape to the cytoplasm finally entering the nucleus
Tropism and epidemiology
– primary infection occurs in childhood, the virus persists in the kidneys
– in cases of immunosuppression, there is reactivation resulting in
hemorrhagic cystitis and BKVAN in bone marrow and kidney transplant recipients respectively
– modes of transmission include fecal-oral, vertical/ transplacental transmission
Role in carcinogenesis
– the oncogenic properties of BKPyV have been demonstrated in in vitro and in vivo experimental models
– 2 viral oncoproteins have been described i.e., large T-antigen (TAg) and small t-antigen (tAg)
– these viral products cause alterations in the normal cell cycle eventually leading to cell immortalization and neoplastic transformation
– Merkel cell polyomavirus has an oncogenic role in merkel cell carcinoma (MCC) which is a rare skin cancer
– BKPyV genetic material has been detected in various cancers like prostate, bladder, renal, brain, osteosarcomas
– there are some arguments for BKPyV carcinogenicity and these include: –
– overall, it has become difficult to demonstrate the carcinogenic role of BKPyV
Conclusion:
– the main challenge is coming uo with strategies that will confirm or exclude the role of BKPyV in carcinogenesis
– more studies are required to answer this question
Level of evidence provided by this article:
Level V
1. Please summarize this article.
This is a Review article
Introduction
· Four of the 14 polyomaviruses (SV40, BKPyV, JCPyV, and MCPyV) have been found to show oncogenic potential.
· Some of these viruses have been found in human tumors, suggesting an etiological relationship with cancer.
· The International Agency for Research on Cancer (IARC) in 2012 reported BKPyV to be “possibly carcinogenic to humans.”
· There is strong evidence of link in the case of MCPyV and Merkel cell carcinoma. A carcinogenic role for SV40 also suspected but the association remains controversial.
· This review explores biological aspects of BKPyV, molecular mechanisms in carcinogenesis and its potential association with human cancers.
Viral entry
· Mainly through respiratory and faeco-oral route.
· BKPyV entry inside the cells is caveolin- and clathrin-independent – may be utilizing an as-yet uncharacterized endocytic pathway.
· Finally, the virus enters the nucleus via the importin-α/β pathway, guided by nuclear localization signals present in the minor capsid proteins VP2 and VP3.
Epidemiology and tropism
· Human polyomaviruses (HPyVs) are ubiquitous.
· After primary infect in early childhood, and remain latent in kidney and urothelium, with potential integration into the host genome. BKPyV genomes have also been detected in a wide spectrum of normal tissues.
· Upon BKPyV infection in a permissive host cell, early gene expression leads to DNA replication, followed by late gene expression, production of progeny viral particles and cell death. In a non-permissive cell, lytic replication is blocked, and abortive infection may result in oncogenic transformation
· Although the oncogenic activity of BKPyV is well documented in laboratory settings, there is no conclusive evidence of a causal relationship between BKPyV and cancer in human beings.
Role in carcinogenesis: (Lab models)
BKV in Renal, bladder and Prostate cancer
· Some studies demonstrate BKPyV DNA sequences at high frequencies in bladder carcinoma. However, these studies were small case series that either lacked a control group or relied entirely on antibody seroprevalence.
· Although associations between BKPyV and these tumors are rare, the virus may have a tumorigenic role in some cases
· possible oncogenic mechanism involves deregulation of the proliferation inducer Tag
Conclusion:
· Exact role of BK virus in human cancer is not clearly discernible.
o more epidemiological and experimental studies are strongly required.
· The possibility of interaction with other host-related factors, infectious agents or environmental components for carcinogenesis warrants more investigation.
2. What is the level of evidence provided by this article?
Level – 5 (Narrative review)
1. Please summarise this article;
BK virus belongs to a family of polyomavirus family, small double-stranded non-enveloped DNA virus, categorized into four groups with different virulence.
SV40 has been weak association with malignancy.
Viral entry;
Its entry is via caveolin and clathrin independent mechanism, when get entrance it proceed to the nucleus for replication via the alpha and beta pathway.
Epidemiology and tropism;
Remain dormant state in epithelial cells of tubular, parietal, transitional structure, and bowman’s capsules.
The incidence of shedding in immunocompetent patient is around 20%, the incidence of shedding of viruria in immunocompromissed recipient is around 60%.
In pregnant women the shedding disappear two weeks after delivery.
The prevalence of BKVN in renal transplant recipient is 5%, primary infection is in first decade life, possible routes droplets (airborne), fecal oral, urinary oral rout, blood born, during renal transmission, trans-placental.
There is no such evidence association BKPyL and malignancy in humans.
Role in carcinogenesis;
The early region encodes BKVPyL genome encodes two viral oncogenic protein Tag the large and the tAg(p53 family protein) the small, they induce alteration in normal cell cycle and possible neoplastic transformation, second, it inhibit protein phosphatase PP2A an essential tumor suppressor gene in cell death signaling pathway.
There is evidence that BKPyV tAg induces chromosomal instability in embryonic fibroblast and tumorigenesis by alteration in deletion, duplication, and translocation.
BKVPyL genome early region detected in Ewings tumor, neuroblastoma, and genitourinary tract tumor, prostate and bladder tumors.
BKVPyL can have association of carcinoma with other associated infection like HPV16 in high grade cervical cancers.
Conclusion;
Need conclusive evidence to confirm the association and exclusion of BKVPyL with carcinomas.
Interaction of infectious agents and environmental components in carcinogenesis.
Level of evidence V
Human polyomaviruses (HPyVs) are small, non-enveloped, double-stranded DNA viruses with approximately 5000-bp genome and icosahedral symmetry.
Viral entry
Role in carcinogenesis:
BKV and bladder cancer
there are reports that link BKPyV with metastatic bladder carcinoma in immunosuppressed transplant recipient
BKV and Ca Prostate:
BKPyV may be implicated in the inactivation of these tumor suppressor proteins at early stages of tumorigenesis
Conclusion:
Though BKV may be “potentially carcinogenic”, to clarify the role of this virus in human cancer, more epidemiological and basic research is strongly warranted.
Level of evidence: Level V (Narrative review)
● Function of BKPyV gene products
☆ Early coding region :
▪︎Large Tumour Antigen (Tag)
” Cell cycle progression, inhibition of apoptosis, viral replication”
▪︎Truncated Large T antigen (truncTAg)
” Cell cycle progression, viral replication ”
▪︎Minor T Antigen (tAg)
” Cell cycle progression ”
3p-miRNA and 5p-miRNA
” viral persistence ”
☆ Late coding region :
▪︎VP1
” capsid structure (external), viral attachment and entry ”
▪︎VP2
” capsid structure (internal), involved in viral infectivity ”
▪︎VP3
” capsid structure (internal), involved in viral infectivity ”
▪︎Agno protein
” Life cycle (assembly, maturation, release)”
● After entering the cell, the virus must reach nucleus for replication.
● Once partial disassembly occurs. Viral particles escape to the cytoplasm
● Virus enters the nucleus by signals in the
minor capsid proteins VP2 and VP3
Epidemiology
● BKPyV seroprevalence of 65–90% in
5–9 year old children
● BKPyV causes hemorrhagic cystitis and
nephropathy (BKAN) in bone marrow and renal transplant patients, respectively
● Fecal-oral transmission and a vertical transmission only in primary BKV infection
● Salivary glands and oropharyngeal cells are not involved in BKPyV persistence
● Once the virus enters to the body,(PBLs) transport BKPyV to different organs
● Although the oncogenic activity of BKPyV is well documented This relationship is difficult to demonstrate for several reasons:
☆ The viral agent has a high prevalence in the general population
☆ There are a wide range of human tissues in which the virus can be detected
☆ The virus has the ability to remain in a latent state for long periods
Role in carcinogenesis
● The early region encodes two viral oncoproteins: (TAg) and (tAg).
These induce alterations in the normal cell cycle leading to cell immortalization and neoplastic transformation
● tAg inhibits protein phosphatase 2A an essential tumor suppressor in numerous death-signaling pathways.
● Although BKPyV TAg modulate cellular growth it needs additional events for complete transformation. These events could be mutations or alterations of the viral promoter-enhancer elements, leading to increased expression of early genes and a consequent increase in transforming activity
● BKPyV TAg induces chromosomal instability in human embryonic fibroblasts, characterized by gaps, breaks, dicentric and ring chromosomes, deletions, duplications and translocations
● The early BKPyV genome region has been detected in brain tumors, Ewing’s tumors, osteosarcomas, , neuroblastomas and genitourinary tract tissues tumors, including prostatic and bladder cancer
● The virus may co-infect cells that were previously infected by another oncogenic virus, increasing susceptibility to cancer.
● Patients who develop PVAN are at significantly higher risk of developing cancers which are high-grade and invasive.
● possible oncogenic mechanism involves deregulation of the proliferation inducer TAg
● Human oncogenic virus such as BKPyV may be implicated in the inactivation of these tumor suppressor proteins at early stages of tumorigenesis
● A carcinogenic role has also been suspected for SV40
● The cytoplasmic localization of oncogenic protiens suggests a functional inactivation mechanism by sequestration
● The “hit-and-run” carcinogenesis mechanism is a possible tumorigenic mechanism in which the TAg inactivates p53 in the atrophic cells, increasing susceptibility to genetic alterations, including tumor suppressor gene mutations that may result in early prostate cancer progression.
● Level evidence : 5
II. Role of BK human polyomavirus in cancer
Summarise this article
Background
– Human polyomaviruses (HPyV) are small DNA viruses belonging to the polyomaviridae family
– 13 distinct HPyVs have been described so far, with some being found in tumors
– HPyV infection occurs early in life through fecal-oral transmission
– 4 polyomaviruses have been found to have oncogenic potential i.e., SV40, BKPyV, JCPyV and MCPyV
– strong evidence only exists for MCPyV which is associated with merkel cell carcinoma, a rare skin cancer
BK virus viral entry
– virus gains entry into the cell thereafter it reaches to the nucleus for replication, once in the endoplasmic reticulum, partial disassembly occurs and the viral particles escape to the cytoplasm finally entering the nucleus
Tropism and epidemiology
– primary infection occurs in childhood, the virus persists in the kidneys
– in cases of immunosuppression, there is reactivation resulting in
hemorrhagic cystitis and BKVAN in bone marrow and kidney transplant recipients respectively
– modes of transmission include fecal-oral, vertical/ transplacental transmission
Role in carcinogenesis
– the oncogenic properties of BKPyV have been demonstrated in in vitro and in vivo experimental models
– 2 viral oncoproteins have been described i.e., large T-antigen (TAg) and small t-antigen (tAg)
– these viral products cause alterations in the normal cell cycle eventually leading to cell immortalization and neoplastic transformation
– Merkel cell polyomavirus has an oncogenic role in merkel cell carcinoma (MCC) which is a rare skin cancer
– BKPyV genetic material has been detected in various cancers like prostate, bladder, renal, brain, osteosarcomas
– there are some arguments for BKPyV carcinogenicity and these include: –
– overall, it has become difficult to demonstrate the carcinogenic role of BKPyV
Conclusion
– the main challenge is coming uo with strategies that will confirm or exclude the role of BKPyV in carcinogenesis
– more studies are required to answer this question
Level of evidence provided by this article
Level V
ROLE OF BKV IN CANCER.
INTRODUCTION.
-HPV are non enveloped ,double stranded DNA with approx 5000bp genome and an icosahedral shape. It contains an early and a late region.
-HPV are normally latent in the host until immunosuppression occurs then thy flare and cause an infection.
-x4 types exist;SV40,BKPyV,JCPyV and MCPyV. The latter has been linked to merkel cell carcinoma.SV40 too has been weakly linked to malignancy.
BK VIRUS.
VIRAL ENTRY;
–Contact btn GD3 and VP1 is key for infection to occur. Viral entry is via caveolin and clathrin independent mechanism. Once in the cell it proceeds ti the nucleus for replication via the importin alpha/beta pathway.
TROPISM AND EPIDEMIOLOGY;
–Primary infection occurs in early childhood with a prevalence of 65-90% in 5-9 yr olds. It would then persist in the kidneys and be deadly once immunosuppression occurs. It has been associated with BKAN and hemorrhagic cystitis in BMT and KTR.
-Amongst other modes of transmission, vertical transmission has been reported, post infection, the virus disseminates to other organs via peripheral blood leukocytes.
-There is no solid evidence linking BKPyV and malignancy in the human population.
ROLE IN CARCINOGENESIS;
-Carcinogenic property is linked to early region that encodes oncoproteins ;TAg and tAg that alter normal cell cycle leading to neoplastic transformation.
TAg interacts with p53 and pRb tumor suppressor proteins ,altering them and interfering with cell cycle with resultant uncontrolled cell proliferation + chromosomal instability.
-tAg blocks PP2A ,activating signal pathways that promote cell proliferation leading to oncogenesis.
-Animals injected with BKPyV have been found to develop ependymomas, pancreatic islet tumors, osteosarcomas, liposarcomas, nephroblastoma, gliomas, HCC and RCC. This is yet to be documented in humans.
-Some authors have found BKPyV genes in brain tumors, osteosarcomas, erwings tumor, neuroblastoma and GUT tumors-Prostate and bladder.
-BKPyV has also been found in an unclear association with HPV16 in high grade cervical squamous intraepithelial lesions. More studies are needed in this.
-Unlike in immunocompetent, immunocompromised have had an association btn BKPyV to metastatic bladder ca partly due to propensity of the virus to reside in urothelial cells.
-In prostate ca, we have mixed results that are inconclusive on contribution of BKPyV to prostate Ca despite extensive research on the same.
CONCLUSION.
Carcinogenic role of thus virus in humans is not yet established and more studies are definitely needed.
LEVEL OF EVIDENCE -5
Role of BK in cancer
Summary
· BKV DNA was found in wide range of tumors as brain tumors, Ewing sarcoma, neuroblastoma and genitourinary tumors as bladder and prostate. However, it is still needing further research to find it is causation or just an association.
· BKV infection was described to increase invasion and aggressiveness of bladder cancer in immunocompromised patients.
· Merkel virus one of polyoma viruses was linked to rare type of skin cancer, Merkel carcinoma.
Level of evidence: Narrative review (level V)
Summary of the article
Role of BK human polyomavirus in cancer
Four polyomaviruses have been found to show oncogenic potential; SV40, BKPyV, JCPyV, and MCPyV.
The transforming activity has been mapped in the early region of the BKPyV genome, which encodes two viral oncoproteins that induce alterations in the normal cell cycle leading to cell immortalization and neoplastic transformation:
· the large T-antigen (TAg).
· the small t-antigen (tAg).
Early BKPyV genome region has been detected in a wide range of human tumors:
· Brain tumors.
· Osteosarcomas.
· Ewing’s tumors.
· Neuro- blastomas.
· Genito-urinary tract tissues tumors including prostatic and bladder cancer.
· High-grade cervical squamous intraepithelial lesions: in association with HPV16.
· MCPyV; appears to play a role in a rare skin cancer, Merkel cell carcinoma.
The level of evidence provided by this article
This is a narrative review article with level of evidence grade 5.
Background :
This review is done to evaluate the molecular mechanisms of BKPyV infection and its potential association with cancer.
Human polyomaviruses (HPyVs) are small, nonenveloped, double-stranded DNA viruses, belong to the polyomaviridae family. It encdes early small-t/large-T antigens as well as late structural proteins called VP1, VP2, VP3, and agnoprotein.
The HPyV capsid harbors 72 pentamers of VP1, which interacts with the VP2/VP3 molecules associated with each pentamer .
HPyV encode a pre-miRNA for generation of two mature miRNAs . A non-coding control region (NCCR) is located between the oppositely-oriented transcriptional units that encode for early and late transcripts. The NCCR contains the promoters and enhancers for regulation of gene expression and harbors the replication origin (Ori) .
In BKPyV, JCPyV, and SV40, the agnoprotein is expressed from the 5’region of VP2 open reading frame. It is believed that this protein is involved in regulating viral gene expression or inducing viral maturation
.
In immunocompetent people the virus remains latent with potential integration into the host genome. while in immunosuppressed patients it may reactivate and establish a productive infection.
HPyV infection typically occurs in childhood , often through fecal-oral transmission, and persists throughout the lifespan.
Fourteen HPyVs have been described, most of which were discovered recently . Four polyomaviruses have been found to show oncogenic potential — SV40, BKPyV, JCPyV, and MCPyV . MCPyV appears to play a role in a rare skin cancer, Merkel cell carcinoma . A carcinogenic role has also been suspected for SV40, but the association remains controversial as no robust evidence has emerged.
BK virus Viral entry:
A specific contact between the terminal sialic acid residue of GD3 and VP1 is essential for virus infection. After entering the cell viral particles escape to the cytoplasm,, then enters the nucleus guided by nuclear localization signals present in the minor capsid proteins VP2 and VP3 .
Tropism and epidemiology:
The primary infection most often occurs in early years of life , with a seroprevalence of 65–90% in 5–9 year old children .
BKPyV persists in the kidneys following primary infection, and reactivated causing significant morbidity when the host becomes immunosuppressed.
BKPyV causes hemorrhagic cystitis in bone marrow transplant and nephropathy (BKAN) in renal transplant patients .
viral transmission is mainly through fecal-oral route . Another mode of transmission is a vertical transmission of this and transplacental transmission .
Once the virus enters the body, probably peripheral blood leukocytes (PBLs) transport BKPyV to different sites and organs .
Upon BKPyV infection in a permissive host cell, early gene expression leads to DNA replication, followed by late gene expression, production of progeny viral particles and cell death. Permissive cells include human embryonic kidney cells or primary human renal proximal tubule epithelial cells and some salivary glands cells .
In a non-permissive cell, BKPyV lytic replication is blocked, and abortive infection may result in oncogenic transformation but there is no conclusive evidence of a causal relationship between BKPyV and cancer in human beings.
Role in carcinogenesis :
The oncogenic properties of BKPyV are well demonstrated in in vitro and in vivo experimental models.
The early region of the BKPyV genome encodes two viral oncoproteins: the large T-antigen (TAg) and the small t-antigen (tAg). These viral products induce alterations in the normal cell cycle, leading to neoplastic transformation .
The most frequently-studied cellular targets of TAg are the p53 family proteins and pRb tumor suppressor proteins. The interaction between BKPyV TAg and p53 results in the inactivation of this protein, interfering with the response to DNA damage and inducing the unscheduled onset of the S-phase .
Therefore, BKPyV TAg drives the cell to override a key cell cycle checkpoint, favoring the accumulation of genetic alterations during each cell replication cycle .In addition, the interaction between BKPyV TAg and pRb leads to the release and nuclear translocation of the E2 factor (E2F) family of transcription factors and subsequent expression of genes, inducing quiescent cells to enter the S-phase.
Another early gene product of BKPyV, the small tAg, plays an important role in transformation by inhibiting protein phosphatase 2A (PP2A), an essential tumor suppressor in numerous death-signaling pathways.
Early reports demonstrated that BKPyV is highly oncogenic in rodents . In addition, animals injected with BKPyV frequently developed ependymomas, pancreatic islet tumors, osteosarcomas, fibrosarcomas, liposarcomas, osteosarcomas, nephroblastomas and gliomas .
BKPyV TAg may modulate cellular growth through direct interactions with critical regulatory proteins but additional events are required for complete transformation. These events could be mutations or alterations of the viral promoter enhancer elements, leading to increased expression of early genes and a consequent increase in transforming activity
Moreover, it has been shown that BKPyV TAg induces chromosomal instability in human embryonic fibroblasts, characterized by gaps, breaks, dicentric and ring chromosomes, deletions, duplications and translocations Consistent with early participation of BKPyV TAg in tumorigenesis, there is evidence that these alterations occur before immortalization .
Various authors have detected BKPyV genetic material in a wide range of human tumors . For instance, the early BKPyV genome region has been detected in brain tumors, osteosarcomas, Ewing’s tumors, neuroblastomas and genitourinary tract tissues tumors, including prostatic and bladder cancer .
In some cases, BKPyV may not be directly involved in the development of cancer, but instead, play a role as a co-factor in the carcinogenic process. The virus may co-infect cells that were previously infected by another oncogenic virus, increasing susceptibility to malignancy .
Recent reports have documented the presence of BKPyV DNA in association with HPV16 in high-grade cervical squamous intraepithelial lesions but further experimental studies are needed .
Renal cancer, urothelial bladder cancer, and prostatic cancer have been extensively studied because BKPyV has a tropism for certain cell types and remains latent or persistent in the kidney and urinary tract .Therefore, carcinomas that affect this anatomical zone are likely candidates for associations with BKPyV.
The contribution of BKPyV to the etiology of bladder carcinoma in immunocompetent individuals is not well established .
Recent findings using deep sequencing analysis from a high-grade BKPyV-associated tumor expressing TAg have revealed viral DNA integrated into the host genome that lead to blockage of viral replication and suggests a concomitant disruption of regulatory feedback signals that control TAg expression.
Prostate cancer( PCa ) is one of the leading causes of cancer deaths in men worldwide, and its relationship with BKPyV infection has been studied by several groups in recent years In this context, it has been postulated that BKPyV constitutes an important factor for early prostate tumorigenesis .
In conclusion : More epidemiological and experimental studies are strongly required. In addition, the possibility of interaction with other host-related factors, infectious agents or environmental components for carcinogenesis warrants more investigation.
level V
Please summarise this article.
Background
Human polyomaviruses (HPyVs) are small, nonenveloped,
double-stranded DNA viruses .These viruses belong to the polyomaviridae family.
– HPyV infection typically occurs early in life, often through fecal-oral transmission, and persists throughout the lifespan .
– Fourteen HPyVs have been described, most of which were discovered in the last few years .
-Four polyomaviruses have been found to show oncogenic potential — SV40, BKPyV, JCPyV, and MCPyV — although there is strong evidence of such a link only in the case of MCPyV. This virus appears to play a role in a rare skin cancer, Merkel cell carcinoma.
BK virus
Tropism and epidemiology
-The primary infection most often occurs in early childhood, with a seroprevalence of 65–90% in 5–9 year old children . Following primary infection, BKPyV persists in the kidneys. If the host becomes immunosuppressed, the virus causes significant morbidity.
-BKPyV causes hemorrhagic cystitis and nephropathy (BKAN) in bone marrow and renal transplant patients, respectively .
-Transmission mechanisms fecal-oral transmission and vertical transmission .
-There is no conclusive evidence of a causal relationship between BKPyV and cancer in human beings.
Role in carcinogenesis
-The oncogenic properties of BKPyV are welldemonstrated
in in vitro and in vivo experimental models.
-The early BKPyV genome region has been detected in brain tumors, osteosarcomas, Ewing’s tumors, neuroblastomas and genitourinary tract tissues tumors, including prostatic and bladder cancer .
– BKPyV may co-infect cells that were previously infected by another
oncogenic virus, increasing susceptibility to cancer. In fact, HPyVs have been detected in various tissues that are susceptible to transformation by HTLV-I, HCV, HPV, EBV, HHV-8 and HBV.
– Recent reports have documented the presence of BKPyV DNA in
association with HPV16 in high-grade cervical squamous intraepithelial lesions.
-studies showed that patients who develop PVAN are at significantly
higher risk of developing cancers, including transitional cell bladder carcinoma .
-Urothelial carcinomas expressing BK TAg are quite rare, these cancers show some distinct features. These tumors are high-grade and invasive. Lesions can arise in the renal allograft or the host urothelial tissue.
-Monini et al. detected BKPyV in approximately 60% of cancerous and healthy prostates, and the viral load was found to be significantly higher in neoplastic as compared to non-neoplastic tissue .
-These apparently contradictory data can be partially explained due to the variable sensitivity and specificity of the detection methods used
in each study.
– it has been postulated that BKPyV constitutes an important factor for early prostate tumorigenesis .
What is the level of evidence provided by this article?
Level 5
BK polyoma virus BKPyv:
infection is one the most important causes of morbidity and mortality post transplantation with specific impact on allograft function and progression of kidney disease.
Polyoma viruses are extremely common , attracted early in life mainly via fecal oral rout, and has reported prevalence of 60-90% by age of 5-9 years.
After primary infection:
BKPyv dwell in the kidney and persevere for years . When the host turned to be immunodeficient, particularly , after kidney transplantation, the virus emerge to replicate and inflict renal diseases in the form of hemorrhagic cystitis and nephropathy reported in the context of bone marrow transplantation and kidney transplantation respectively.
Rout of BKPyv infection:
Rout of transmission is usually fecal -oral. After entering to the body , peripheral blood Leukocytes transport the virus to different organs and tissues.
Infection of permissive cells:
When infection permissive cells infected, early gene experssion , leads to DNA replication. with consequent late gene expression, production of progeny viral particles and cell death.
Permissive cells for viral infection, are salivary glands cells , renal proximal epithelial cells.
Non infection permissive cells:
In those cells BKPyv replication is blocked , abortive infection might results in oncogenic transformation.However, There is no definite relation between BKPyv infection and malignancy.
The relationship is difficult to ascertain due to several factors:
1] BKPyv is extremely prevalent in population.
2 ] BKPyv is widely spead in different human tissues.
3 ]BKPyv is inherently latent for longer duration with occasional activation.
Nevertheless, There were an irrefutable experimental evidences of the oncogenesity of BKPyv, attributable to its two oncoproteins larg T protein[TAg] and small t protein[tAg], which are inflicting alteration in cell cycle resultant in neoplastic transformation.
Merkel Cell Polyoma virus MCPyV:
The only exception is MCPyV which is evidently linked to rare skin cancer Merkel cell carcinoma.
This is a review with level evidence of 5.
14 types of polyomavirus have been discovered until recently. Some of which were reported to have an association with malignancy. Relation to cancer became an interest because o the wide spread of this family. Oncogenicity was mostly related in HPyV, MCPyV, HPyV.
BK virus infection starts in childhood. Seroprevalence up to 65-90% before the age of 10. Post-infection it stays in the kidney. But BK was also documented in plenty of tissues like the liver, lymph nodes, brain, saliva etc. The faecal-oral route is the most believed way of infection.
Trasnformin (oncogenic) activity of BK was reported in experimental studies. The large T-antigen (TAg) and small t- antigen (t-Ag) were shown to cause alterations in the cell cycle, but the causality needs to be checked and controlled by more robust controlled studies.
Table 2 in the paper shows details about evidence with/against the carcinogenic role.
……
I agree with your analysis of the level of evidence this article provides.
I wish you could type headings and sub-headings as underline or in bold.
Introduction:
Human polyoma viruses are small non-enveloped double stranded DNA viruses that have an icosahedral shape. These viruses are ubiquitous and belong to the polyoma viridae family. The genome consists of approximately 5000 base pairs. The human polyoma virus codes for:
Early Small-t/large-T antigens as well as late structural proteins called VP1, VP2, VP3 and agno-proteins. The early region, which is transcribed before the DNA replication begins, is composed of large T and small t antigen genes and the splice variants T=135, T=136 and T=165. The late region is transcribed concomitant with DNA replication. The human polyoma virus capsid harbors 72 pentamers of VP1 which interact with VP2/VP3 molecules associated with each pentamer. In addition, these viruses encode a pre-miRNA for generation of 2 mature miRNAs.
In natural hosts, human polyoma viruses establish a productive infection, while in heterologous, non-permissive hosts, the virus establishes latency with potential integration into the host genome. Human polyoma virus infection occurs early in childhood, mainly through the feco-oral route. Four polyoma viruses have been found to show oncogenic potential:
The only strong evidence is only found in the case of merkel cell polyoma virus
BK Virus:
Using siRNA strategy, it was demonstrated that the virus entry caveolin- and clathrin independent. These findings together with the fact that the virus entry does not require actin polymerization, excludes other endocytic pathways and suggests that BKV utilizes an as-yet uncharacterized endocytic pathway.
Once in the ER, partial disassembly occurs. Viral particles escape to the cytoplasm, hijacking ER Derlin family proteins. Finally, the virus enters the nucleus via the importing-alpha/beta pathway, guided by nuclear localization signals present in the minor capsid proteins VP2 and VP3
Tropism and epidemiology:
BK virus infection mostly occurs in childhood, with a seroprevalence of 65-90% in 5-9 year old children. Following primary infection, the virus persists in the kidneys. When the host becomes immunosuppressed, the virus causes significant morbidity. It can cause hemorrhagic cystitis and BKVN in HSCT and renal transplant patients respectively.
Once the virus enters in the body, probably peripheral blood leucocytes (PBLs) transport it to the different sites and organs.
Although the oncogenic activity of BKV is well documented in laboratory settings, there is no conclusive evidence of a causal relationship between BKV and cancer in humans. This relationship is difficult to demonstrate in ecological contexts due to several reasons:
Role In Carcinogenesis:
The oncogenic properties of the BK virus are well demonstrated in in vitro and in vivo experimental models. The transforming activity has been mapped in the early region of the BKV genome which encodes two viral oncoproteins: the large T antigen and the small t antigen. These viral products induce alterations in the normal cell cycle, ultimately leading to cell immortalization and neoplastic transformation.BKV large TAg is a highly multifunctional protein that can bind various cellular proteins, altering signaling pathways involved cell cycle control. The most frequently studied cellular targets of TAg are the p53 family proteins and the pRb tumor suppressor proteins. The interaction between BKV TAg and p53 results in inactivation of this protein, interfering with the response to DNA damage and inducing the unscheduled onset of the S-phase. The interaction between BKV TAg and pRb leads to the release and nuclear translocation of the E2 factor family of transcription factors and subsequent expression of genes, inducing quiescent cells to enter the S phase.
Although the transforming ability of the BKV is well documented in experimental rodent models, definitive transforming activity is not always observed in humans and primates.
Various authors have detected BKV genetic material in a wide range of tumors including brain tumors, osteosarcomas , Ewings tumors, neuroblastoma and genitourinary tract tissue tumors including prostate and bladder cancer. In contrast, other authors have not reported an association between BKV DNA and tumors
in any case, the mere presence of BKV DNA does not necessarily reflect a neoplastic involvement of the virus.
There are reports that link BKV to metastatic bladder cancer in transplant recipients. In a retrospective study, Roberts et al reported that while no positive BKV TAg urothelial carcinomas were found in a series of of non-trasnplanted patients, strong nuclear staining for TAg was seen in the urothelial carcinoma of one transplanted patient. This data indicates that although associations between BKV and these tumors are rare, the virus may have a tumorigenic role in some cases.
Prostate cancer is one of the leading causes of cancer deaths in men worldwide, and its relationship with BKV infection has been studied by several groups in recent years. Monin et al detected BKV in approximately 60% of cancerous and healthy prostates, and the viral load was found to be significantly higher in neoplastic as compared to non-neoplastic tissue. Lau et al, using in situ, detected BKV in only 2/30 prostate adenocarcinomas and no TAg expression was detected in neoplastic tissue.
Conclusion:
BKV is a polyoma virus that has a high prevalence in the young and has a tropism for the renal tubular cells and urothelium. There have been in vitro studies showing the association between BKV and tumorigenesis. It has been difficult to establish a causality between BKV and tumors as majority of patients have already been infected by the virus. More robust studies need to be done to establish a relationship between BKV and cancers
Level of evidence: Systematic review – level of evidence V
I agree with your analysis, summary and level of evidence this article provides.I appreciate your views on carcinogenic potential of BKV.
Summary
Background
Human polymaviruses are small non-enveloped double stranded DNA with icosahedral symmetry that belong to the polyomaviridae family.
HPyV infection occur early in childhood with the fecal oral route of transmission and tend to last one”s lifespan.
Currently 14 HPyV have been identified with 4 associated with malignancies, however only MCPyV has strong oncogenic link evidence. MCPyV is associated with Merkel cell carcinoma which is a rare skin cancer.
Tropism and epidemiology.
BKPyV primary infection occurs in early childhood with seroprevalence rates of 65-90% in 5-9 year olds. After primary infection it remains latent in the kidneys. When the host immunity is compromised it causes hemorrhagic cystitis and BKVAN in both bone marrow and renal transplant recipients respectively.
BKPyV infection in a permissive cell leads to gene expression and DNA replication, while infection in a non-permissive cell leads to oncogenic transformation.
Though BKPyV oncogenic properties have been demonstrated in laboratory studies there has been no conclusive evidence of causal relationship in human beings. This is due to the fact that BKPyV has a high prevalence in general population, it can be detected in various tissue and its ability to remain latent for a long period of time.
Role in carcinogenesis
The transforming properties have been mapped out in the early region of the BKPyV genome which codes for viral oncoprotein large T antigen and small t antigen.
This viral proteins induce changes in the normal cell cycle leading to cell immortalisation and neoplastic transformation.
The BKPyV T antigen is a multifunctional protein that can bind various cellular proteins thus altering signalling pathways that are involved in cell cycle control. Most studied is its interaction with p53 and pRb tumour suppressor proteins.
Interaction with p53 leads to its inactivation and induces the cell to unscheduled S-phase.
Interaction with pRb leads to release and nuclear translocation of E2 factor inducing cells to enter S phase.
BKPyV small t antigen inhibits protein phospholipase A2 which is a tumour suppressor.
Although transforming ability of BKPyV has been demonstrated in rodents, definitive transformation lacks in humans and primates.
Studies have shown conflicting results with some reporting an association of BKPyV and tumours and others showing no association.
However the mere presence of BKPyV DNA doesn’t not necessary indicate a neoplastic involvement. In other instances BKPyV may not be playing a direct role but rather a co-factor in the carcinogenic process
Conclusion
Further studies are required to confirm or exclude the role of BKPyV in the development of tumours.
Level of evidence:V
I agree with your analysis, summary and level of evidence this article provides.I appreciate your views on carcinogenic potential of BKV.
Introduction ;
————————————
Human polyomaviruses (HPyV), which are small DNA viruses classified into the polyomaviridae family, are widely distributed in human populations. Thirteen distinct HPyVs have been described to date. Some of these viruses have been found in human tumors, suggesting an etiological relationship with cancer.
Early findings established that BKPyV has a tropism for certain cell types and that this agent can establish a persistent or latent infection in the kidney and urinary tract .Therefore, carcinomas that affect this anatomical zone are likely candidates for associations with BKPyV.
The viral oncoproteins:
—————————————————-
1-The large T-antigen (TAg)
2-The small t-antigen (tAg).
These viral products induce alterations in the normal cell cycle, ultimately leading to cell immortalization and neoplastic transformation .
BKPyV large Tag;
——————————–
Is a highly multifunctional protein that can bind various cellular proteins, altering signaling pathways involved in cell cycle control. The most frequently-studied cellular targets of TAg are the p53 family proteins and pRb tumor suppressor proteins.
The small tAg;
——————————
Plays an important role in transformation by inhibiting protein phosphatase 2A (PP2A), an essential tumor suppressor in numerous death-signaling pathways.
The oncogenic activity of BKPyV;
—————————————————
Although the oncogenic activity of BKPyV is well- documented in laboratory settings, there is no conclusive evidence of a causal relationship between BKPyV and cancer in human beings. This relationship is difficult to demonstrate in ecological contexts for several reasons:
1-The viral agent has a high prevalence in the general population.
2-there are a wide range of human tissues in which the virus can be detected .
3- The virus has the ability to remain in a latent state for long periods, with occasional reactivations.
Evidences of BKPyV carcinogenicity
————————————————————–
1- Viral oncogenes are expressed in tumors.
2- Tumors developed in in vivo model.
3- Transforming properties in in vitro models.
4- BKPyV alterations occur before immortalization .
5- BKPyV genome detected in human tumors .
Evidences for a non-carcinogenic role ;
———————————————————–
1- Poor and not efficient transforming activity in human cells.
2- Ubiquitous distribution in normal human cells and tissues.
3- Variable BKPyV presence in tumors among different studies.
Conclusion;
————————-
Thus, more epidemiological and experimental studies are strongly required. In addition, the possibility of interaction with other host-related factors, infectious agents or environmental components for carcinogenesis warrants more investigation.
What is the level of evidence provided by this article?
Level V
That is a well-structured reply.
Typing the whole sentence in bold amounts to shouting, however.
Please summarise this article.
# The aim of the study:
*To determine the molecular mechanisms of human polyomaviruses (BKPyV) infection and its relation with malignancy .
# Introduction:
* (HPyVs) are small, non enveloped, dsDNA viruses, it is belong to the polyomaviridae family.
*The HPyV genome encodes early small-t/large-T antigens as well as late structural proteins called VP1, VP2, VP3, and agnoprotein.
*In natural hosts, HPyVs establish a productive infection, while in heterologous, non-permissive hosts, the virus establishes latency with potential integration into the host genome.
*14 HPyVs have been described and 4 polyomaviruses showed oncogenic potential SV40, BKPyV, JCPyV, and MCPyV (MCPyV with strong cancer relation).
* A carcinogenic role has also been suspected for SV40, but the association remains controversial.
# Tropism and epidemiology:
*The primary infection commonly occurs during early childhood, with a seroprevalence of 65–90% in 5–9 year old.
*After primary infection, BKPyV persists in the kidneys, and when the host becomes immunosuppressed, it lead to morbidity.
*It results in hemorrhagic cystitis in BMT and (BKAN) in renal transplantation.
*BKPyV genomes can be found in normal tissues.
*The transmission via fecal-oral route, vertical and transplacental transmission
*In spite of oncogenic effect of BKPyV that had been detected in laboratory context, there is no clear evidence of a causal relationship between BKPyV and malignancies in human beings.
# Role in carcinogenesis:
*The oncogenic properties of BKPyV are well demonstrated in vitro and in vivo experimental models.
* The BKPyV genome, encodes two viral oncoproteins:
Large,T-antigen
Small t-antigen can induce alterations in the normal cell cycle, result in neoplastic transformation.
*BKPyV large TAg is a highly multifunctional protein
that can bind various cellular proteins, altering signaling
pathways involved in cell cycle control.
*Animals injected with BKPyV frequently developed different types of tumors.
*Although the transforming ability of BKPyV is well documented in experimental rodent models, definitive
transforming activity is not always observed in human
and primates
*BKPyV TAg induces chromosomal instability in human embryonic fibroblasts, characterized by gaps, breaks, dicentric and ring chromosomes, deletions, duplications and translocations.
# Evidences of BKPyV carcinogenicity:
*Viral oncogenes are expressed in tumors.
*Tumors developed in in vivo models.
* Transforming properties in in vitro models.
*BKPyV alterations occur before immortalization
*BKPyV genome detected in human tumor.
# Evidences for a non-carcinogenic role:
*Poor and not efficient transforming activity in human cells.
*Ubiquitous distribution in normal human cells and tissues.
*Variable BKPyV presence in tumors among different studies.
# Conclusion
*Conclusive evidence is required to allow confirmation or exclude the role of BKPyV in the development of tumors. *More epidemiological and experimental studies are strongly required.
*The possibility of interaction with other host-related factors, infectious agents or environmental components for carcinogenesis warrants more investigation.
# What is the level of evidence provided by this article?
*Level V
I agree with your analysis, summary and level of evidence this article provides.I appreciate your views on carcinogenic potential of BKV.
Please summarise this article.
Background
BK virus
Viral entry
Tropism and epidemiology
Role in carcinogenesis
Conclusion
====================================================
What is the level of evidence provided by this article?
I agree with your analysis, summary and level of evidence this article provides.I appreciate your views on carcinogenic potential of BKV.
This article address the molecular mechanisms of BKPyV infection and its potential association with cancer.
BK virus is Human polyomaviruses (HPyVs) are small, non- enveloped, dsDNA viruses.
The HPyV genome encodes early small-t/large-T antigens as well as late structural proteins called VP1, VP2, VP3, and agno- protein.
The agnoprotein is expressed from the region of VP2 and it’s responsible for control of HPyV life cycle.
It’s occur in early life from feco- oral transmission.
There’s Four polyomaviruses that show evidence of oncogenic potential — SV40, BKPyV, JCPyV, and MCPyV and there’s strong association with developing of cancer especially skin cancer and Merkel cell carcinoma.
The SV40 is suspected to be association with cancer but still under studies.
Tropism and epidemiology:
The primary infection mainly occurs in early childhood, with a seroprevalence of 65–90% in 5–9 year- old children.
If the patients becomes immunocompromised the primary infection will be persist in the kidney and causes significant morbidity. The BKPyV may causes hemorrhagic cystitis in bone marrow transplant and BK nephropathy in renal transplant patients.
The virus presents in almost of tissue and mode of transmission by feco oral and many studies shows vertical transmission in seronegative pregnant women.
There’s strong evidence of oncogenic activity of BKPyV but still upto now no conclusive relationship between BKPyV and cancer and it’s may be due to presence of reasons as fallow//
First: the viral agent has a high prevalence in the general population;
Second: there are a wide distribution of virus to human tissues
Third: the virus has the ability to remain in a latent state for long periods, with occasional reactivations.
Role in carcinogenesis:
The oncogenic genes of BK V are well demonstrated in vitro and vivo experimental models.
The transforming activity is recognised in the early region of the BKPyV genome, which encodes two viral oncoproteins: the large T-antigen (TAg) and the small t-antigen (tAg). This oncoprotein bind to different cellular proteins in different tissue of body and any alteration of these function may predispose to formation of cancer.
Many studies shows that BKPyV is highly oncogenic in rodents. They showed injected animal with BKPyV frequently developed ependymomas, pancreatic islet tumors, osteosarcomas, fibrosarcomas, liposarcomas, osteosarcomas, nephro- blastomas and gliomas.
Experimental study done for mice to express transgenic BKPyV shows early genome region were develop highly tissue specific tumors.
Few studies shows these animals developed primary hepatocellular carcinomas and renal tumors, thymuses and renal adenocarcinomas.
BK V TAg may lead to random mutational events which activate cellular oncogenes or inactivate other tumor suppressor genes.
However, some studies shows no association between BKPyV DNA and tumors.
There’s many conflict studies regarding the role of BKPyV in bladder cancer. Prostatic cancer are common cancer in male and it’s relation with BKV still under studies.
Conclusion:
The role of BKV in developing of cancer still under studying and still not proved. So it’s need further experimental studies.
Level V
I appreciate your views on carcinogenic potential of BKV. I agree with your analysis, summary and level of evidence this article provides.
Please summarise this article.
Introduction:
Viral entry
Tropism and epidemiology
1. The virus is highly prevalent in the general population.
2. Wide range of human tissues were the virus can be detected.
3. The ability of the virus to remain in a latent state for long periods, with occasional reactivations.
Role in carcinogenesis
Conclusion
Ability of interaction of BKPyV with other host-related factors, infectious agents or environmental components for carcinogenesis, and needs more investigation, and studies.
What is the level of evidence provided by this article
The level of evidence provided by this article V- erratic review
I agree with your analysis, summary and level of evidence this article provides.I appreciate your views on carcinogenic potential of BKV.
The word ‘Narrative review’ has been mistyped in your last sentence
II. Role of BK human polyomavirus in cancer
====================================================================
Please summarise this article.
Background
====================================================================
BK virus
Viral entry
Tropism and epidemiology
====================================================================
Role in carcinogenesis
====================================================================
Conclusion
====================================================================
What is the level of evidence provided by this article
The level of evidence provided by this article V
I agree with your analysis, summary and level of evidence this article provides.I appreciate your views on carcinogenic potential of BKV.
Many thanks Prof.Sharma
Summary
Introduction
Human polyomaviruses is dsDNA virus, its genome codes for early region antigen (t and T antigen and late (VP1, VP2 and VP3 )antigen and agnoprotein which is involved in various functions related to the HPyV life cycle, such as regulating viral gene expression or inducing viral maturation
Infection occur mostly early childhood and become latent with the mode of transmission is mainly fecooral root and there is evidence of transplacental transmission as well
Four polyomaviruses have been found to be carcinogenic — SV40, BKPyV, JCPyV, and MCPyV — which is linked to Merkel cell carcinoma
Tropism and Epidemiology
· As stated above infection started early in childhood by age of 9 > 90 % get infected
· After infection virus become dormant in kidneys ( its cell permit viral replication and called permissive cells )and various tissue ( liver , stomach, cervix , vulva , vagina , bladder, lips and tongue
· Under immunosuppression status, it regains activity and may cause BKVAN in kidney transplant and hemorrhagic cystitis in HSCT
· In a non-permissive cell, BKPyV lytic replication is blocked, and abortive infection may result in oncogenic transformation
Role in carcinogenesis
The rule of BKPyV as carcinogenic factor proved both in vitro and in vivo. it is related for early antigen region ( t and T ) which alter cell cycle and immortalize the cell and cause oncogenic transformation.
BKPyV large Tag has the ability of binding various cell protein interrupting normal cell cycle like P53 and bRp protein leading to their in activation hence leading the cell to enter into S- phase and this favors the accumulation of genetic alterations during each cell replication cycle
Additionally, the interaction between BKPyV TAg and pRb leads to the release and nuclear translocation of the E2 factor (E2F) family of transcription factors and subsequent expression of genes, inducing quiescent cells to enter the S-phase
On the other hand, The small tAg, inhibit protein phosphatase 2A (PP2A), an essential tumor suppressor in numerous death-signaling pathways and can activate signaling pathways that promote cell proliferation, such as mitogen-activated protein kinase (MAPK)
So, animals injected with BKPyV frequently developed ependymomas, pancreatic islet tumors, osteosarcomas, fibrosarcomas, liposarcomas, osteosarcomas, nephroblastomas and gliomas, primary hepatocellular carcinomas and renal tumors in Small trials while in Dalrymple and Beemon trial they report enlarged thymuses and renal adenocarcinomas.
In human this transforming activity is not always observed as had been identified in SV40 virus oncogenicity that may be explained by lower expression levels of the BKPyV promoter and enhancer elements, which share only 40% homology with the SV40 promoter region
Oncogenicity that occasionally happen with BCV may be de to p53 inactivation by BK TAg may lead to random mutational events that could activate cellular oncogenes or inactivate
The finding of the virus in tumor tissue does not mean its involvement in its development but may act as a co-factor in the carcinogenic process for example, recent reports have documented the presence of BKPyV DNA in association with HPV16 in high-grade cervical squamous intraepithelial lesions
The propensity of the BKV to urothelial cells raise the question of its involvement in the tumorigenesis .in a retrospective review by Chen et al. reported that 6/864 patients developed polyomavirus-associated nephropathy (PVAN). Malignancy occurred in 5/6 PVAN patients, suggesting that patients who develop PVAN are at significantly higher risk of developing cancers, including transitional cell bladder carcinoma in addition , These tumors are high-grade and invasive
Regarding involvement of BKV in prostatic cancer reports are contradictory but it has been postulated that BKPyV constitutes an important factor for early prostate tumorigenesis through early suppression of P 35 and bRp poteins
Conclusion
more epidemiological and experimental studies are strongly required to confirm or exclude the role of BKPyV in the development of tumors.
I appreciate your views on carcinogenic potential of BKV. I agree with your analysis of this article
Role of BK human polyomavirus in cancer
Journal: Infectious Agents and Cancer (2018)
Levican and his group.
Human polyomaviruses are small DNA viruses have been found in human tumors and etiological relationship was proven with Merkel cell polyomavirus which linked to rare skin cancer, Merkel cell carcinoma (MCC). KPyV-mediated human carcinogenesis.
BKPyV structure and its function:
· Early Large Tumour Antigen (Tag): Cell cycle progression, inhibition of apoptosis, viral
replication.
· Minor T Antigen (tAg): Cell cycle progression.
· 3p-miRNA and 5p-miRNA: viral persistence.
· Late VP1: capsid structure (external), viral attachment and entry.
· VP2, VP3 capsid structure (internal): involved in viral infectivity.
· Agno protein Life cycle: assembly, maturation, release.
Although the oncogenic activity of BKPyV is proven in laboratory settings, there is no conclusive evidence of a causal relationship between BKPyV and cancer in human. This relationship is difficult to proven as:
1. high prevalence of the virus in the general population with no associated malignancy.
2. a wide range of human tissues in which the virus can be detected.
3. the virus has the ability to remain in a latent state for long periods.
4. the virus may co-infect cells that were previously infected by another oncogenic virus like HTLV-I, HCV, HPV, EBV, HHV-8 and HBV, increasing susceptibility to cancer
The oncogenic properties of BKPyV are well-demonstrated in in vitro and in vivo experimental
models.There are two viral oncoproteins: the large T-antigen (TAg) and the small t-antigen (tAg). These viral products induce alterations in the normal cell cycle, ultimately leading to cell immortalization and neoplastic transformation
· BKPyV large TAg targets the p53 family proteins and pRb tumor suppressor proteins results in the inactivation of this protein causing DNA damage.
· BKPyV TAg drives the cell to override a key cell cycle check-point, favoring the accumulation of genetic alterations during each cell replication cycle.
· the small tAg inhibiting protein phosphatase 2A (PP2A), an essential tumor suppressor in numerous death-signaling pathways.
In Vitro
cells cultured from kidney or brain tissues with complete or sub-genomic fragments of BKPyV DNA, containing the early coding region, lead to oncogene-induced neoplastic transformation
In Vivo
Animal studies:
BKPyV is highly oncogenic in rodent as inoculated with the virus showed developed tumors at various locations that contained BKPyV DNA sequences
animals injected with BKPyV frequently developed ependymomas, pancreatic islet tumors, osteosarcomas, fibrosarcomas, liposarcomas, osteosarcomas, nephroblastomas and gliomas.
In humans:
definitive transforming activity is not always observed in human. The transformation by BKPyV is not efficient and is often abortive, and features of the transformed phenotype are not fully displayed
BCS: BKPyV TAg activity is lower in BKPyV-infected BSC cells and its expression by BKPyV is not sufficient to completely capture the Rb family of proteins
bladder carcinoma:
in a retrospective review of kidney transplant patients on 6/864 patients developed polyomavirus-associated nephropathy (PVAN). Malignancy occurred in 5/6 PVAN patients suggesting that patients who develop PVAN are at significantly higher risk of developing cancers
in a multi-center study done on 114 transitional bladder carcinoma cases and a group of 140 hospital controls which showed no role of BKPyV in bladder cancer among immunocompetent individuals.
Prostate cancer (PCa):
Prevalence study done by Monini et al. detected BKPyV in approximately 60% of cancerous and healthy prostates,and the viral load was found to be significantly higher in neoplastic as compared to non-neoplastic tissue.
Lau et al., using in situ, detected BKPyV in only 2/30 prostatic adenocarcinomas, and no TAg expression was detected in neoplastic tissue.
Similarly, Sfanos et al. of 338 analyzed total samples from 200 patients for BKPyV DNA and detected only one positive sample.
Conclusion
BK virus relation to human malignancies like bladder and prostatic cancer is not proven yet and more epidemiological and basic research is still needed.
I agree with your analysis, summary and level of evidence this article provides.I appreciate your views on carcinogenic potential of BKV.
thanks Professor Ajay
Please summarise this article.
Human Polyomavirus HPvY has been associated with development of malignancies. HPyY has been associated with skin cancer and , Merkel cell carcinoma (MCC). This review is about the BK virus BKPyV infection from a historical point of view, including biological aspects related to viral entry, tropism, epidemiology and mechanisms potentially involved in BKPyV-mediated human carcinogenesis.
Tropism and epidemiology
The primary infection most often occurs in early childhood, with a seroprevalence of 65–90% in 5–9 year old.
Following primary infection, BKPyV persists in the kidneys. If the host becomes immunosuppressed, the virus causes significant morbidity.
Transmission can be feco oral, trnasplacental or by vertical route.
Currently there no significant evidence of association with BKPyV and malignancy.
Role in development of malignancy
The oncogenic properties of BKPyV are welldemonstrated in in vitro and in vivo
Two viral oncoproteins: the large T-antigen (TAg) and the small t-antigen (tAg)
The interaction between BKPyV TAg and p53 results in the inactivation of this protein, interfering with the response to DNA damage and inducing the unscheduled onset of the S-phase
Transforming ability of BKPyV is welldocumented in experimental rodent models, definitive transforming activity is not always observed in human
Inactivation of tumour suppressor gene has a role .
Alteration in chromosomal activity
Main association with bladder and prostate cancer.
Conclusion
· At the moment there is no conclusive evidence of role of BKPyV in the development of cancer
· The investigative strategies that might lead to conclusive evidence that would allow us to confirm or exclude the role of BKPyV in the development of tumours are required
Level of evidence V
☆Role of BK human polyomavirus in cancer
____________________________________
▪︎This review evaluated the molecular mechanisms of BKPyV infection and its potential association with cancer.
◇ Background
▪︎Human polyomaviruses (HPyVs) are small, nonenveloped, double-stranded DNA viruses belong to the polyomaviridae family.
▪︎In natural hosts, HPyVs establish a productive infection, while in heterologous, non-permissive hosts, the virus establishes latency with potential integration into
the host genome. HPyV infection typically occurs early in life, often through fecal-oral transmission, and persists throughout the lifespan.
▪︎Fourteen HPyVs have been described, four of them have been found to
show oncogenic potential — SV40, BKPyV, JCPyV, and MCPyV — although there is strong evidence of such a link only in the case of MCPyV in a rare skin cancer, Merkel cell carcinoma.
▪︎A carcinogenic role has also been suspected for SV40, but the association remains controversial.
BK virus
▪︎A specific contact is essential for virus infection.
▪︎ After entering the cell, the virus must reach the nucleus for replication.
The primary infection most often occurs in early childhood, with a seroprevalence of 65–90% in 5–9 yearold children. Following primary infection, BKPyV persists in the kidneys.
▪︎If the host becomes immunosuppressed, the virus causes significant morbidity.
It is transmitted by fecal-oral and vertical
Upon BKPyV infection in a permissive host cell, early gene expression leads to DNA replication, followed by late gene expression, production of progeny viral particles and cell death. Permissive cells for viral replication are kidney cells. In addition, it has been reported that some salivary glands cells are permissive for
◇ BKPyV infection
▪︎ In a non-permissive cell, BKPyV lytic replication is blocked, and abortive infection may result in oncogenic transformation.
▪︎Although the oncogenic activity of BKPyV is well documented in laboratory settings, there is no conclusive evidence of a causal relationship between BKPyV and cancer in human beings.
This relationship is difficult to demonstrate in ecological contexts for several reasons:
1. The viral agent has a high prevalence in the general population.
2. There are a wide range of human tissues in which the virus can be detected.
3. The virus has the ability to remain in a latent state for long periods, with occasional reactivations.
◇ Role in carcinogenesis
▪︎The transforming activity of the BK virus has been mapped in the early region of the BKPyV genome, which encodes two viral oncoproteins:
1. The large T-antigen (TAg)
2. The small t-antigen (tAg)
▪︎These viral products induce alterations in the normal cell cycle, ultimately leading to
cell immortalization and neoplastic transformation.
▪︎BKPyV large TAg can bind various cellular proteins (eg: p53), altering signaling pathways involved in cell cycle control. In addition, it can induceg quiescent cells to enter the S-phase by interaction with pRb
▪︎ The small tAg, inhibit the tumor suppressor protein phosphatase 2A (PP2A),
▪︎Although the transforming ability of BKPyV is well documented in experimental rodent models, definitive transforming activity is not always observed in human and primates.
▪︎Integration of early-region viral sequences into the host genome has
been shown to account for the difference between serum-independent growth and full transformation in BKPyV-infected human embryonic kidney cells.
▪︎P53 inactivation by BK TAg may lead to random mutational events that could activate cellular oncogenes or inactivate other tumor suppressor genes.
▪︎Various authors have detected BKPyV genetic material in a wide range of human tumors (brain tumors, osteosarcomas, Ewing’s tumors, neuroblastomas and genitourinary tract tissues tumors, including prostatic and bladder cancers. In
contrast, other authors reported no association between BKPyV DNA and tumors.
▪︎The virus may play a role as a co-factor
in the carcinogenic process.
▪︎The contribution of BKPyV to the etiology of bladder carcinoma in immunocompetent individuals is not well established. On the other hand, there are reports that link BKPyV with metastatic bladder carcinoma in immunosuppressed transplant recipients.
strong nuclear staining for TAg was seen in the urothelial carcinoma of one
renal transplant patient.
▪︎Patients who develop PVAN are at significantly higher risk of developing cancers, including transitional cell bladder carcinoma.
▪︎BKPyV constitutes an important factor for early prostate tumorigenesis.
But ispite of all The carcinogenic role of this virus has been difficult to demonstrate.
◇ Conclusion
▪︎This review explores the BKPyV infection from a historical point of view, including biological aspects related to viral entry, tropism, epidemiology and mechanisms potentially involved in BKPyV-mediated human carcinogenesis.
▪︎ In order to clarify the role of this virus in human cancer, more epidemiological and basic research is strongly warranted.
☆ Level of Evidence: Level V
This is a review article
I appreciate your views on carcinogenic potential of BKV. I agree with your analysis, summary and level of evidence this article provides.
Please summarise this article.
What is the level of evidence provided by this article?
I agree with your analysis, summary and level of evidence this article provides.
I wish you could type headings and sub-headings as underline or in bold.
Role of BK human polyomavirus in cancer
Background:
Viral entry:
Role in carcinogenesis
Conclusion:
Level of evidence: is 5
I agree with your analysis, summary and level of evidence this article provides.I appreciate your views on carcinogenic potential of BKV.
Role of BK human polyomavirus in cancer
Summary of This Article.
Human polyomaviruses are small, nonenveloped, double-stranded DNA viruses belong to the polyomaviridae family are prevalent in human populations.
there genome encodes have early coding region, late coding region
and non-coding control region NCCR.
Around 14 poliomaviruses have been discovered.
Four viruses have been found to have oncogenic potential — SV40, BKPyV, JCPyV, and MCPyV.
Both Skin cancer and Merkel cell carcinoma are strongly linked to MCPyV.
Some of these viruses have been discovered in human malignancies, indicating an
etiological link between these viruses and cancer.
BKPV virus was assessed for carcinogenicity by the International Agency for Research
on Cancer (IARC) in 2012, & IARC concluded that BKPV is “possibly carcinogenic to
humans.”
More epidemiological & basic research is required to uncover the part played by this
virus in human cancer.
BKV:
The BKPV Genome
Function of BKPV gene products:
Oncogenicity:
Role of BKPV in carcinogenesis:
Evidence of BKPV carcinogenicity
Evidence for a non-carcinogenic role
Conclusion
BKPyV may have a role in the development of tumors
Further studies are strongly required
Other possible carcinogenic related factors (host-related factors, infectious agents, or environmental components) warrant more investigation
The carcinogenic role of the virus is difficult to demonstrate for many reasons:
1- the viral agent has a high prevalence in the general populations
2- there are a wide range of human tissues in which the virus can be detected
3- The virus could remain in a latent state for long periods, with occasional reactivations.
Level of evidence V => (Review article)
I appreciate your views on carcinogenic potential of BKV. I agree with your analysis, summary and level of evidence this article provides.
1. Please summarise this article.
Introduction
The BKPV Genome
Function of BKPV gene products:
Oncogenicity:
Role of BKPV in carcinogenesis:
Evidence of BKPV carcinogenicity
Evidence for a non-carcinogenic role
=============================
2. What is the level of evidence provided by this article?
I agree with you analysis, summary and level of evidence this article provides.
The role of the BK virus in cancer:
Introduction:
BK virus is a small DNA virus belonging to polyomavirus, and the primary infection most commonly happens in early pediatric age, but in immunocompetent population, it mostly doesn’t cause clinical disease, while in immunocompromised patient the dormant virus, replicate and reactivated and it may cause BK viremia and BKVN.
Role in carcinogenesis:
1. The large T-antigen (TAg).
2. The small t-antigen (tAg).
Conclusion:
Level of evidence:
Level((V)) review
I agree with you analysis, summary and level of evidence this article provides.
1-Please summarise this article?
Introduction;.
-Human polyomaviruses (HPyV), which are small DNA viruses classified into the polyomaviridae family, are widely distributed in human populations.
-Thirteen distinct HPyVs have been described to date. Some of these viruses have been found in human tumors, suggesting an etiological relationship with cancer.
-In particular, convincing evidence of an oncogenic role has emerged for a specific HPyV, the Merkel cell polyomavirus (MCPyV). This HPyV has been linked to rare skin cancer, Merkel cell carcinoma (MCC).
-Four polyomaviruses have been found to show oncogenic potential — SV40, BKPyV, JCPyV, and MCPyV,
Role in carcinogenesis;
-The oncogenic properties of BKPyV are welldemonstrated in in vitro and in vivo experimental models.
-The transforming activity has been mapped in the early region of the BKPyV genome, which encodes two viral oncoproteins: the large T-antigen (TAg) and the small t-antigen (tAg).
-These viral products induce alterations in the normal cell cycle, ultimately leading to cell immortalization and neoplastic transformation.
-In addition, the interaction between BKPyV TAg and pRb leads to the release and nuclear translocation of the E2 factor (E2F) family of transcription factors and subsequent expression of genes, inducing quiescent cells to enter the S-phase.
-Various authors have detected BKPyV genetic material in a wide range of human tumors.
-For instance, the early BKPyV genome region has been detected in brain tumors, osteosarcomas, Ewing’s tumors, neuroblastomas and genitourinary tract tissues tumors, including prostatic and bladder cancer.
-In contrast, other authors reported no association between BKPyV DNA and tumors. In any case, the mere presence of BKPyV DNA does not necessarily reflect a neoplastic involvement of the virus.
-The association of BKPyV with precancerous cervical lesions suggests that this virus could be involved in HPV16-induced cell transformation.
-The contribution of BKPyV to the etiology of bladder carcinoma in immunocompetent individuals is not well established. Some studies demonstrate BKPyV DNA sequences at high frequencies in bladder carcinoma.
-Prostate cancer (PCa) is one of the leading causes of cancer deaths in men worldwide, and its relationship with BKPyV infection has been studied by several groups in recent years.
Conclusion;.
-The challenge now is to devise investigative strategies that might lead to conclusive evidence that would allow us to confirm or exclude the role of BKPyV in the development of tumors.
-Thus, more epidemiological and experimental studies are strongly required.
-In addition, the possibility of interaction with other host-related factors, infectious agents or environmental components for carcinogenesis warrants more investigation.
2-What is the level of evidence provided by this article?
level V evidence.
I agree with you analysis, summary and level of evidence this article provides.
Role of BK human polyomavirus in cancer.
Background.
The HPyV genome encodes early small-t/large-T antigens as well as late structural proteins called VP1, VP2, VP3, and Agno protein. In BKPyV, JCPyV, and SV40, the Agno protein is expressed from the 5’region of VP2 open reading frame.
HPyV infection typically occurs early in life, often through fecal-oral transmission, and persists throughout the lifespan, Four polyomaviruses have been found to show oncogenic potential which are SV40, BKPyV, JCPyV, and MCPyV. This virus (MCPyV.) appears to play a role in a rare skin cancer, Merkel cell carcinoma.
BK virus.
A specific contact between the terminal sialic acid residue of GD3 and VP1 is essential for virus infection, virus entry does not require actin polymerization, exclude other known alternative endocytic pathways and suggests that BKPyV utilizes an as-yetun characterized endocytic pathway. Finally, the virus enters the nucleus via the importin-!/” pathway, guided by nuclear localization signals present in the minor capsid proteins VP2 and VP3.
Tropism and epidemiology.
The primary infection most often occurs in early childhood, with a seroprevalence of 65–90% in 5–9 year old children and then persists in the kidneys, later on it might cause hemorrhagic cystitis and nephropathy (BKAN) in bone marrow and renal transplant patients, transmitted by multiple routes such as faeco-oral, respiratory, organ transplantation, and Transplacental.
Role in carcinogenesis.
The large T-antigen (TAg) and the small t-antigen (tAg). These viral products induce alterations in the normal cell cycle, ultimately leading to cell immortalization and neoplastic transformation, The most
frequently-studied cellular targets of TAg are the p53 family proteins and pRb tumor suppressor proteins and this lead to inducing the unscheduled onset of the S-phase, all theses experimental studies such as animals injected with BKPyV frequently developed ependymomas, pancreatic islet tumors, osteosarcomas, fibro sarcomas, lip sarcomas, osteosarcomas, nephroblastomas and gliomas. An alternative model for the role of BKPyV TAg in oncogenesis involves the first step in which BKPyV Tag binds to or inactivates tumor suppressor proteins, with a second step leading to cellular oncogene activation. It is controversial till now, Various authors have detected BKPyV genetic material in a wide range of human tumors . For instance, the early BKPyV genome region has been detected in brain tumors, osteosarcomas, Ewing’s tumors, neuroblastomas and genitourinary tract tissues tumors, including prostatic and bladder cancer . In contrast, other authors reported no association between BKPyV DNA and tumors, other theory that the association between oither oncogenic virus might be the cause of ontogenesis such as the association of BKPyV with precancerous cervical lesions suggests that this virus could be involved in HPV16-induced cell transformation. Some studies demonstrate BKPyV DNA sequences at high frequencies in bladder carcinoma but no large randomized control studies confirmed that, the relation between the BKPyV and cancer prostate is still controversial as a possible tumorigenic mechanism in which the TAg inactivates p53 in the atrophic cells, increasing susceptibility to genetic alterations, including tumor suppressor gene mutations that may result in early prostate cancer progression.
Conclusion.
Still, there is no robust evidence about the role of BKPyV and progression of different types of tumors and its role in carcinogenesis and more investigational studies needed to confirm or exclude that.
Level of evidence:V.
I agree with you analysis, summary and level of evidence this article provides.
Please summarise this article.
Introduction
The HPyV genome encodes for:
1. Early small-t/large-T antigens (transcribed before DNA replication begins)
2. Late structural proteins called VP1, VP2, VP3, and agnoprotein (transcribed concomitant with DNA replication.)
3. Pre-miRNA for generation of two mature miRNAs
Agnoprotein protein may be involved in various functions related to the HPyV life cycle, such as regulating viral gene expression or inducing viral maturation
Four polyomaviruses show oncogenic potential (SV40, BKPyV, JCPyV, and MCPyV)
Strong evidence of cancer link is only in MCPyV (Merkel cell carcinoma)
Aim of the study:
Address the molecular mechanisms of BKPyV infection and its potential association with cancer
Viral entry
· During BKPyV infection, VP1 interacts with gangliosides and the complex ganglioside GD3 is formed
· BKPyV utilizes an as-yetuncharacterized endocytic pathway
· After entering the cell, the virus reach the nucleus for replication [This process depends on acidification and maturation of the endosome and involves retrograde transit of endocytic vesicles to the endoplasmic reticulum (ER)]
· At the end, the virus enters the nucleus via the importin-α/β pathway, guided by nuclear localization signals present in the minor capsid proteins VP2 and VP3
Tropism and epidemiology
BKPyV genomes detected in kidney, bone marrow, liver, stomach, lungs, parathyroid glands, lymph nodes, brain, peripheral blood mononuclear cells, bladder, uterine cervix, vulva, prostate, lips and tongue
Route of transmission: fecal-oral transmission, vertical transmission (only in primary BKV infection), and transplacental
BKPyV infection in a permissive host cell: early gene expression leads to DNA replication, followed by late gene expression, production of progeny viral particles and cell death
Permissive cells are:
1. Kidney cells such as Vero (African green monkey kidney), HEK293 (human embryonic kidney cells) or RPTE (primary human renal proximal tubule epithelial cells)
2. Some salivary glands cells
Non-permissive cell: BKPyV lytic replication is blocked, and abortive infection may result in oncogenic transformation
The relationship between BKPyV and cancer in human is difficult to demonstrate because of:
1. The viral agent has a high prevalence in the general population
2. Second, there are a wide range of human tissues in which the virus can be detected
3. The virus has the ability to remain in a latent state for long periods, with occasional reactivations
Role in carcinogenesis
o The large T-antigen (TAg) and the small t-antigen (tAg) induce alterations in the normal cell cycle, and ultimately leading to cell immortalization and neoplastic transformation
o BKPyV large TAg is a highly multifunctional protein binds various cellular proteins, altering signaling pathways involved in cell cycle control (p53 family proteins and pRb tumor suppressor proteins)
o The small tAg, plays an important role in transformation by inhibiting protein phosphatase 2A (PP2A), an essential tumor suppressor in numerous death-signaling pathways
o Transforming in BKPyV is well documented in experimental animals, but definitive transforming activity is not always observed in human
o BKPyV has a tropism for certain cell types like kidney and urinary tract (so, renal cancer, urothelial bladder cancer, and prostatic cancer are likely associated)
Evidences of BKPyV carcinogenicity:
1. Viral oncogenes are expressed in tumors
2. Tumors developed in in vivo models
3. Transforming properties in in vitro models
4. BKPyV alterations occur before immortalization
5. BKPyV genome detected in human tumors
Evidences for a non-carcinogenic role:
1. Poor and not efficient transforming activity in human cells
2. Ubiquitous distribution in normal human cells and tissues
3. Variable BKPyV presence in tumors among different studies
Conclusion
· BKPyV may have a role in the development of tumors
· Further studies are strongly required
· Other possible carcinogenic related factors (host-related factors, infectious agents or environmental components) warrant more investigation
What is the level of evidence provided by this article?
Level V
I agree with you analysis, summary and level of evidence this article provides.
Background
-Human polyomaviruses are small, nonenveloped, double-stranded DNA viruses belong to the polyomaviridae family. there genome encodes have
early coding region,
late coding region
and non-coding control region NCCR.
Around 14 poliomaviruses have been discovered.
Four viruses have been found to have oncogenic potential — SV40, BKPyV, JCPyV, and MCPyV.
-Both Skin cancer and Merkel cell carcinoma are strongly linked to MCPyV.
Viral entry
A crystal-like complex of VP1 and ganglioside GD3 is formed with several points of contact between VP1 and two sialic molecules of a disialic acid ganglioside.
This model was tested using site-directed mutagenesis.
Using a siRNA strategy, it was demonstrated that BKPyV entry is caveolinand clathrin-independent. The virus must reach the nucleus for replication. This process depends on acidification and maturation of the endosome and involves retrograde transit of endocytic vesicles to the endoplasmic reticulum.
The virus enters the nucleus via the importin-α/β pathway, guided by nuclear localization signals present in the minor capsid proteins VP2 and VP3.
Role in carcinogenesis:
The oncogenic role was demonstrated in vivo and in vitro. Rodents infected with this virus showed the development of tumors at various locations that contained BKV DNA sequences, either integrated into the host genome or in a free episomal form with constitutive TAg expression. Experimental suggest that while BKV TAg may modulate cellular growth through direct interactions with critical regulatory proteins, additional events (mutations) are required for complete transformation. Also, they linked the transformation activites to the higher expression of Ha-ras oncogen and inactivation of P53 tumor suppressor gene.
In human:
Various authors have detected the early BKV genome region in brain tumors, osteosarcomas, Ewing’s tumors, neuroblastomas and genitourinary tract tissues tumors, including prostatic and bladder cancer. The contribution of BKV to the etiology of bladder carcinoma in immunocompetent individuals is not well-established. Some linked it to metastatic disease In prostate cancer, some authors reported significantly higher expression of BKV presence in malignant cells compared to non-malignant cells. This was not proven in other cases. Based on genetic studies, some postulated that BKV infection implicated suppression of tumor suppressor genes. the TAg inactivates p53 in the atrophic cells, increasing susceptibility to genetic alterations, including tumor suppressor gene mutations that may result in early prostate cancer.
In conclusion,
the carcinogenic role of the virus is difficult to demonstrate for many
reasons:
II- level of evidence: V
I agree with you analysis, summary and level of evidence this article provides.
Background
Human polyomaviruses are small, nonenveloped, double-stranded DNA viruses with approximately 5000-bp genome and icosahedral symmetry.
These viruses belong to the polyomaviridae family.
The HPyV genome encodes early small-t/large-T antigens as well as late structural proteins called VP1, VP2, VP3, and agnoprotein.
The HPyV capsid harbors 72 pentamers of VP1, which interacts with the VP2/VP3 molecules associated with each pentamer .
These viruses encode a pre-miRNA for generation of two mature miRNAs.
Four polyomaviruses have been found to show oncogenic potential —SV40.BKPyV, JCPyV, and MCPyV — there is strong evidence of such a link only in the case of MCPyV
This virus appears to play a role in a rare skin cancer, Merkel cell carcinoma. This review evaluates the molecular mechanisms of BKPyV infection and its potential association with cancer
Viral entry
A crystal-like complex of VP1 and the ganglioside GD3 is formed, with several points of contact between VP1 and two sialic molecules of a disialic acid ganglioside.
This model was tested using site-directed mutagenesis.
Using a siRNA strategy, it was demonstrated that BKPyV entry is caveolinand clathrin-independent.
The virus must reach the nucleus for replication.
This process depends on acidification and maturation of the endosome and involves retrograde transit of endocytic vesicles to the endoplasmic reticulum.
The virus enters the nucleus via the importin-α/β pathway, guided by nuclear localization signals present in the minor capsid proteins VP2 and VP3.
Tropism and epidemiology
BKPyV infection is a widely-distributed strict anthroponosis.
The primary infection most often occurs in early childhood, with a seroprevalence of 65–90% in 5–9 year old children.
If the host becomes immunosuppressed, the virus causes significant morbidity.
BKPyV causes hemorrhagic cystitis and nephropathy (BKAN) in bone marrow and renal transplant patients, respectively.
BKPyV genomes have been detected in a wide spectrum of normal
BKPyV expression product function
Large tumor antigen Cell cycle progression, inhibition of apoptosis, viral replication truncated Large T antigen Cell cycle progression, viral replication.
The transmission mechanism is not completely elucidated, the high resistance of BKPyV to environmental inactivation and its presence at high concentrations in human sewage and other water sources suggest fecal-oral transmission.
In this respect, it was reported that salivary glands and oropharyngeal cells are not involved in BKPyV persistence, suggesting that digestive tract would be important for viral transmission.
Showed a vertical transmission of this virus only in the case of primary BKV infection of serologically negative pregnant women.
It was reported the presence of BKPyV in 7 out 10 specimens of aborted fetuses suggesting the possibility of transplacental transmission.
It has been reported that some salivary glands cells are permissive for BKPyV infection.
This relationship is difficult to demonstrate in ecological contexts for several reasons: first, the viral agent has a high prevalence in the general population; second, there are a wide range of human tissues in which the virus can be detected; and third, the virus has the ability to remain in a latent state for long periods, with occasional reactivations
Role in carcinogensis
The oncogenic properties of BKPyV are well demonstrated in in vitro and in vivo experimental models.
These events could be mutations or alterations of the viral promoter enhancer elements, leading to increased expression of early genes and a consequent increase in transforming activity.
In support of this model, integration of early-region viral sequences into the host genome has been shown to account for the difference between serum-independent growth and full transformation in BKPyV-infected human embryonic kidney cells.
This integration event could result in positioning of BKPyV TAg coding sequence under the control of nearby cellular promoter-enhancer elements.
Findings
Monini et al detected BKPyV in approximately 60% of cancerous and healthy prostates, and the viral load was found to be significantly higher in neoplastic as compared to non-neoplastic tissue.
Conclusion
The challenge now is to devise investigative strategies that might lead to conclusive evidence that would allow us to confirm or exclude the role of BKPyV in the development of tumors.
More epidemiological and experimental studies are strongly required.
The possibility of interaction with other host-related factors, infectious agents or environmental components for carcinogenesis warrants more investigation
Level of evidence is 5
I agree with you analysis, summary and level of evidence this article provides.
1- Summary:
BK virus:
Role in carcinogenesis:
In human:
In conclusion, the carcinogenic role of the virus is difficult to demonstrate for many
reasons:
1- the viral agent has a high prevalence in the general populations
2- there are a wide range of human tissues in which the virus can be detected
3- The virus has the ability to remain in a latent state for long periods, with occasional
reactivations.
II- level of evidence: V
I agree with you analysis, summary and level of evidence this article provides.
SUMMARY
Introduction
Human polyomaviruses are small nonenveloped double-stranded DNA viruses, and about thirteen distinct human polyomaviruses have been described to date. Some of these human polyomaviruses have also been linked with an association with the development of various types of cancer cells in different parts of the human body.
The majority of the infection usually takes place early in life but remains dormant till a state of immunosuppression supervened. The four human polyomaviruses implicated to be oncogenic are; SV40, BKPyV, JCPyV, and MCPyV. BKPyV has been associated with uroepithelia cancer, MCPyV is implicated in some rare skin cancer, and SV40 role in causing cancer is still yet to be substantiated.
The article aims to review the potential role of BKPyV infection in causing cancer
Tropism and epidemiology
Role of BKPyV in carcinogenesis
Conclusion
There is a need for more epidemiological studies to be done to ascertain the relationship between BKPyv and the development of cancer
Level of evidence is 5
I agree with you analysis, summary and level of evidence this article provides.
Introduction and epidemiology
Human polyomavirus is a sdall, double-stranded, non-enveloped DNA viruses . Six viral proteins—two early, one agnoprotein, and three late proteins—are encoded by its genome.
There are more than 13 different forms of polyomaviruses, however only SV40, BKPyV, JCPyV, and MCPyV may be connected to cancer.
With the exception of MCPyV, which has a strong association with the rare skin disease Markel cell carcinoma, the oncogenic potential of polyomaviruses is currently under debate.
Most people acquire BK infection during childhood, typically through feco-oral or vertical transmission; infection affects the uroepithelium and renal tubules, and is lifelong. Seropositivity occurs in 65–90% of people globally by the ages of 5–9 years.
The majority of BK virus infections are asymptomatic, however they can occasionally manifest with hemorrhagic cystitis (often seen in HSCT) or BK nephropathy.
Role in carcinogenesis
In vivo and in vitro research demonstrates the oncogenicity of BKPyV. The big T-antigen (TAg) and the little T are two viral oncoproteins that are encoded in the early region of the BKPyV genome (tAg). These viral products alter cell division, immortilizing, and neoplasticizing cells.
In hamster embryo cells at early passages, a recombinant construct containing the BKPyV TAg gene and the activated c-Ha-ras oncogene also more effectively induced neoplastic transformation than independently transfected genes, suggesting a cooperative effect of the two oncogenes in early carcinogenesis.
Several biological proteins may bind to BKPyV-big TAg, which would impair cell cycle signaling networks. The tumor suppressor proteins p53 and pRb are the targets of TAg.
When BKPyV TAg inactivates p53, it interferes with the DNA damage response and prematurely enters the S-phase.
Early research revealed that BKPyV may cause chronic or latent kidney and urinary tract infections and has a preference for specific cell types. BKPyV may therefore be related to carcinomas in this region. Numerous studies have been conducted on prostatic, urothelial bladder, and renal malignancies.
Recent studies have shown that high-grade cervical squamous intraepithelial lesions include BKPyV DNA together with HPV16.
Conclusion
There is no compelling evidence of a causal connection between BKPyV and human cancer. Therefore, additional research is necessary.The connection between carcinogenesis and other host-related variables must be studied.
Level of evidence: narrative review level 5
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Please summarize this article.
Role of BK virus in carcinogenesis:
What is the level of evidence provided by this article?
I agree with you analysis, summary and level of evidence this article provides.
no conclusive evidence of a causal relationship between BKPyV and cancer in human
sources of transmission
Role in carcinogenesis
BKPyV & bladder carcinoma in immunocompetent individuals
Prostate cancer
a retrospective review of kidney transplant patients
Chen et al. reported that 6/864 patients developed polyomavirus-associated nephropathy (PVAN). Malignancy occurred in 5/6 PVAN patients, finding suggests that the possible oncogenic mechanism involves deregulation of the proliferation inducer TAg
Why level 3?
LEVEL 5
NOTED
THANKS
Background
-Human polyomaviruses (HPyVs) are small, nonenveloped, double-stranded DNA viruses belong to the polyomaviridae family.
-The HPyV genome encodes early coding region, late coding region and non-coding control region NCCR.
-Around 14 HPyVs discovered. Four viruses have been found to show oncogenic potential — SV40, BKPyV, JCPyV, and MCPyV.
-Skin cancer and Merkel cell carcinoma are strong linked to MCPyV.
BK virus
Viral entry
Various proteins are involved in various functions related to the HPyV life cycle, such as regulating viral gene expression or inducing viral maturation and replication.
Tropism and epidemiology
-HPyV infection typically occurs early in life as primary infection with prevalence 65-90% , and persists throughout the lifespan.
-In immunocompromised individuals, virus reactivation cause significant morbidities e.g; hemorrhagic cystitis and BKAN in HSCT and KTRs.
– Transmission routes: feco-oral, respiratory, vertical transmission.
– Once the virus enters to the body, transport to different permissive host cell kidney and salivary gland.
– In a non-permissive cell, BKPyV lytic replication is blocked, and abortive infection may result in oncogenic transformation.
– There is no conclusive evidence of a causal relationship between BKPyV and cancer in human beings.
Role in carcinogenesis
*Tumors developed in vivo models
-The transforming ability of BKPyV is well documented in experimental animal models. Animals injected with BKPyV frequently developed cancer.
*Transforming properties in vitro models
* BKPyV alterations occur before immortalization
-The early region of genome, which encodes two oncoproteins the large TAg & small T-antigen (tAg) induce alterations in the normal cell cycle, leading to cell immortalization and neoplastic transformation.
– TAg interact with p53 results in its inactivation, interfering with the response to DNA damage and inducing onset of the S-phase.
– TAg interact with pRb leads to the release and nuclear translocation of the E2 factor and inducing quiescent cells to enter the S-phase.
-tAg inhibiting protein phosphatase 2A (PP2A), an essential tumor suppressor in numerous death-signaling pathways.
-TAg binds to or inactivates tumor suppressor proteins, with a second step leading to cellular oncogene activation.
-TAg induces chromosomal instability in human embryonic fibroblasts, these alterations occur before immortalization.
* Viral oncogenes are expressed in tumors
* BKPyV genome detected in human tumors
– HPyVs play a role as a co-factor in the carcinogenic process. It has been detected in various tissues that are susceptible to transformation by HTLV-I, HCV, HPV, EBV, HHV-8 and HBV.
-Some studies demonstrate BKPyV DNA sequences at high frequencies in bladder carcinoma and prostate Ca.
– “hit-and run” carcinogenesis mechanism, the loss of BKPyV in the tumor cells could be due to selection against TAg by the immune system, dilution of viral episomes due to lack of replication or pro-apoptotic effects mediated
Evidence for a non-carcinogenic role:
– Poor and not efficient transforming activity in human cells
– Ubiquitous distribution in normal human cells and tissues
– Variable BKPyV presence in tumors among different studies
Conclusion
There is no conclusive evidence of a causal relationship between BKPyV and cancer in human beings. Therefore, more studies are required.
The interaction with other host-related factors for carcinogenesis need to be investigated.
Level of evidence: narrative review level 5
I agree with you analysis, summary and level of evidence this article provides.
Background:
HPyVs are tiny, nonenveloped, double-stranded DNA viruses having icosahedral symmetry. They’re polyomaviridae. HPyV encodes early small- and large-T antigens and the late structural proteins VP1, VP2, VP3, and agnoprotein. Large T and small t antigen genes and the splice variants T = 135, T = 136, and T = 165 are transcribed before DNA replication. DNA replication transcribes the late region. 72 VP1 pentamers interact with VP2/VP3 molecules in the HPyV capsid. These viruses produce two mature miRNAs from a pre-miRNA.
-HPyVs produce productive infections in native hosts but latency and possible genome integration in heterologous, non-permissive hosts. Early fecal-oral transmission of HPyV leads to lifelong infection. Fourteen HPyVs have been found in the previous several years using high-throughput sequencing methods.
BK entry:
VP1 attaches cells to BKPyV through α2, 8-SA-containing b-series gangliosides (GD1b/GT1b). VP1 forms a crystal-like combination with GD3, a disialic acid ganglioside, and two sialic molecules. Site-directed mutagenesis tested this model. The terminal sialic acid residue of GD3 must touch VP1 for viral infection.
Tropism and epidemiology:
Strict anthroponosis BKPyV is widespread. The seroprevalence is 65–90% in 5–9-year-olds, indicating early infection. Kidneys harbor BKPyV after initial infection. When immunosuppressed, the virus causes considerable morbidity. In bone marrow and kidney transplant patients, BKPyV induces hemorrhagic cystitis and BKAN.
The transmission route is unknown, although BKPyV’s great resistance to environmental inactivation and large quantities in human sewage and other water sources imply fecal-oral transmission. Since salivary glands and oropharyngeal cells do not survive BKPyV, the digestive system may be critical for viral transmission.
Carcinogenesis:
In vitro and in vivo experiments show that BKPyV is oncogenic. The early portion of the BKPyV genome encodes two viral oncoproteins, the big T-antigen (TAg) and the small T. (tAg). These viral products affect the cell cycle, immortalizing, and neo-plasticizing cells.
A recombinant construct containing the BKPyV TAg gene and the activated c-Ha-ras oncogene also induced neoplastic transformation at early passages in hamster embryo cells more efficiently than independently transfected genes, suggesting a cooperative effect of the two oncogenes in early carcinogenesis.
BKPyV-big TAg may bind several cellular proteins and disrupt cell cycle signaling pathways. TAg targets the p53 and pRb tumor suppressor proteins.
BKPyV TAg inactivates p53, disrupting the DNA damage response and triggering the S-phase prematurely.
Early studies showed that BKPyV has a tropism for particular cell types and may cause chronic or latent kidney and urinary tract infections. Thus, BKPyV may be linked to carcinomas in this area. Renal, urothelial bladder, and prostatic cancers have been widely investigated.
Evidence of BKPyV carcinogenicity:
–Viral oncogenes are expressed in tumors
-Tumors developed in vivo models
-Transforming properties in vitro models
-BKPyV alterations occur before immortalization
-BKPyV genome detected in human tumors
Evidence for a non-carcinogenic role:
–Poor and not efficient transforming activity in human cells
-Ubiquitous distribution in normal human cells and tissues
-Variable BKPyV presence in tumors among different studies
Conclusion :
Now we need to find ways to prove or disprove BKPyV’s participation in tumor formation. Epidemiological and experimental investigations are needed. Carcinogenesis may involve host-related factors, infectious pathogens, or environmental variables.
What is the level of evidence provided by this article?
Narrative review, level V
I agree with you analysis, summary and level of evidence this article provides.
1.Please summarize this article.
Introduction:
Epidemiology:
Role in carcinogenesis:
Conclusion:
2.What is the level of evidence provided by this article?
Background
BKV is a double-stranded DNA viruses with 5000-bp genome.
It consists of 3 regions including
-the early region, that is transcribed before DNA replication ,composed of large T and small t antigen genes and the splice variants T = 135, T = 136,and T = 165 .
-The late region is transcribed concomitant with DNA replication
-A non-coding control region (NCCR) is located between the oppositely-oriented transcriptional units that encode for early and late transcripts.
In natural hosts, BKV causes a productive infection, and in non-permissive hosts, the virus is latent with potential integration into the host genome.
BKV infection occurs early in life and persists throughout the lifespan.
There are 14 Human polyomavirus types detected and their association with cancer is studied .
Particularly MCPyV appears to have a role in a rare skin cancer, Merkel cell carcinoma also SV40 seems to have a carcinogenic role but is still controversial.
BK virus
Viral entry
A specific contact between the terminal sialic acid residue of GD3 and VP1 is needed for virus infection.
BKPyV entry is caveolin- and clathrin-independent, BKPyV utilizes an uncharacterized endocytic pathway.
When the virus enters the cell to start replication retrograde transit of endocytic vesicles to the endoplasmic reticulum occurs , then partial disassembly occurs.
The virus enters the nucleus via the importin-α/β pathway.
Tropism
The primary infection usually occurs early in life and the virus remains latent then if the host becomes immunocompromised the virus is activated .
BKPyV causes hemorrhagic cystitis in bone marrow transplants and nephropathy in renal transplant cases.
Feco oral route ,vertical transmission are infection methods
Once BKPyV infect a permissive host cell, early gene expression leads to DNA replication,late gene expression and cell death.
Kidney and salivary gland cells are permissive for the BKV infection.
In non-permissive cells, BKPyV abortive infection can have oncogenic transformation.
Till now the causative relation of BKPyV to cancer is unconclusive
Carcinogenic role
BKPyV carcinogenic effects are detected in vitro and in vivo experimental models but this oncogenic effect is not always detcetd in humans .
The early region of the BKPyV genome harbours the transformation ability leading to cell immortalization and carcinogenesis .
BKPyV large TAg is a multifunctional protein which bind various cellular proteins, changing signaling pathways and it targets p53 family proteins and pRb tumor suppressor proteins.
A difference between SV40 and BKPyV TAg activity was notice and could be attributed to lower expression levels of the BKPyV promoter and enhancer elements.
Another model caould be that the role of BKPyV TAg in oncogenesis involves BKPyV Tag binding to or inactivates tumor suppressor proteins as p53 ,then leading to cellular oncogene activation.
It was declared by some studies that BKPyV genetic material was detected in multiple human tumors as brain and Ewing tumors ,on the contrary this was denied by other studies.
BKPyV can have an indirect role in carcinogenesis acting as a cofactor as there was an association between BKPyV and precancerous cervical lesions.
More studies are needed to clarify if a certain transformation mechanism involving BKPyV and HPV occurs in cervical cancer.
BKPyV has a tropism for some cell types establishing persistent or latent infection in the kidney and urinary tract leading to renal cancer, bladder cancer, and prostatic cancer.
Another study concluded that polyomavirus-associated nephropathy (PVAN) can increase malignancy risk.
The possible oncogenic mechanism is deregulation of the proliferation inducer Tag.
BKPyV codes a miRNA which can be complementary to Tag coding mRNA.
Studies are assessing if these miRNAs are functional during BKPyV infection and if it has a role in BKPyV induced transformation.
Data on the role of BKPyV in cancer prostate is contradictory.
A possible tumorigenic mechanism was suggested where TAg inactivates p53 in the atrophic cells , leading to tumor suppressor gene mutations that may result in early prostate cancer.
Conclusion
More studies are needed to evaluate the BKV role in tumorigenesis either confirm or deny .
-level of evidence is V
Human polyoma virus are DNA virus.
Genome encodes small t/ Large T antigens, late structural proteins called VP1, VP2, VP3 and agnoprotein.
VP1 binds to GD3 of cell – endosome – endocytic vesicles -ER – partial dissassembly- Viral particle escape to the cytoplasm – hijacking ER proteins – virus enters the nucleus.
Role in carcinogenesis
genome encodes 2 viral oncoproteins – Tantigen large and small t antigen – induce alteration in normal cell cycle – leads to cell immortalisation and neoplastic transformation
BkV Tag protein interacts with p53 and inhibits it ,thus interfering response to DNA damage, inducing unscheduled onset of the S phase – accumulation of genetic alterations .
BKV Tag also interacts with pRb – nuclear translocation of E2 factor – genes expressed – induce quiscent cells to enter Sphase.
tAg inhibits PP2 A a tumour suppressor gene – promotes cell proliferation via MAPK.
In addition mutation or alteration of viral promoter enhanced elements leading to Increased expression of early genes with a increase in transforming activity.
Alternative model – BKV Tag binds to or inactivate tumour suppressor proteins P53 with as a second step leading to cellular oncogene activation Ha-ras.
BKX Tag induces chromosomal instability.
BKV genome has been detected in brain tumours,Osteosarcomas, Ewing’s tumour,neuroblastomas, genitourinary tract tissue tumours.
In some cancers Bay genome may play role as a cofactor.
HPyVs may act as a cofactor to H TLV-1, HCV,HPV, E BV,HHV-8 and HBV.
HPyVs along with H PV-16 is seen in precancerous cervical cells.
BKPyV is linked to metastatic bladder Carcinoma in immunosuppressed transplant recepient.
BKPyV constitutes an important factor for early prostrate tumorigenesis.
Evidence for BKPyV Carcinogenicity
Viral oncogenes are expressed in tumours.
BKPyV alteration occur before immortalisation
BKPyV genome detected in human tumour.
Tumours developed in vivo models.
level 5 evidence.
I agree with you analysis, summary and level of evidence this article provides.
I agree with you analysis, summary and level of evidence this article provides.