Evolution of the BK polyomavirus: epidemiological, anthropological and clinical implications

Yogo, Yoshiaki; Sugimoto, Chie; Zhong, Sen; Homma, Yukio

doi:10.1002/rmv.613

Cited by 59 publications

(45 citation statements)

References 84 publications

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“…The possibility that commonly used PCR primers do not robustly detect non-genotype I BKVs (particularly in the case of individuals coinfected with multiple BKV genotypes) is consistent with our observation that BKV-II seroprevalence (Fig. 2) is about 20-fold higher than prior PCR-based prevalence estimates (17,25). A recent report by Chehadeh and Nampoory may also illustrate the problem of older BKV-I-biased PCR results (41).…”

Section: Discussionsupporting

confidence: 89%

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BK Polyomavirus Genotypes Represent Distinct Serotypes with Distinct Entry Tropism

Pastrana

Ray

Magaldi

et al. 2013

J Virol

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BK polyomavirus (BKV) causes significant urinary tract pathogenesis in immunosuppressed individuals, including kidney and bone marrow transplant recipients. It is currently unclear whether BKV-neutralizing antibodies can moderate or prevent BKV disease. We developed reporter pseudoviruses based on seven divergent BKV isolates and performed neutralization assays on sera from healthy human subjects. The results demonstrate that BKV genotypes I, II, III, and IV are fully distinct serotypes. While nearly all healthy subjects had BKV genotype I-neutralizing antibodies, a majority of subjects did not detectably neutralize genotype III or IV. Surprisingly, BKV subgenotypes Ib1 and Ib2 can behave as fully distinct serotypes. This difference is governed by as few as two residues adjacent to the cellular glycan receptor-binding site on the virion surface. Serological analysis of mice given virus-like particle (VLP)-based BKV vaccines confirmed these findings. Mice administered a multivalent VLP vaccine showed high-titer serum antibody responses that potently cross-neutralized all tested BKV genotypes. Interestingly, each of the neutralization serotypes bound a distinct spectrum of cell surface receptors, suggesting a possible connection between escape from recognition by neutralizing antibodies and cellular attachment mechanisms. The finding implies that different BKV genotypes have different cellular tropisms and pathogenic potentials in vivo. Individuals who are infected with one BKV serotype may remain humorally vulnerable to other BKV serotypes after implementation of T cell immunosuppression. Thus, prevaccinating organ transplant recipients with a multivalent BKV VLP vaccine might reduce the risk of developing posttransplant BKV disease. BK polyomaviruses (BKVs or BKPyVs) are a species of icosahedral, nonenveloped, double-stranded DNA viruses. The genomes of all known full-length isolates of BKV can be categorized into four discrete genotypes based on analyses of nucleotide sequences (1). The prevalence and sequence characteristics of each genotype are thought to vary within different human populations worldwide (2).Studies indicate that 83 to 98% of individuals show serum antibody responses to the BKV genotype I (BKV-I) major capsid protein, VP1, by the time they are 21 years of age (3). The virus is thought to establish a lifelong chronic infection in the urinary epithelium, and virions are periodically shed at low levels in the urine of 5 to 27% of healthy adults (4, 5). Although BKV-I can cause malignancy in animal model systems, conclusive evidence showing a causal connection between BKVs and human cancer is still lacking (reviewed in reference 6). While it remains uncertain whether BKVs cause pathology in healthy individuals, it is clear that certain T cell-immunosuppressed individuals, such as recipients of kidney or bone marrow transplants, are at risk of developing uncontrolled BKV replication that leads to nephropathy or hemorrhagic cystitis, respectively (reviewed in reference 7). Currently available antiv...

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Section: Discussionsupporting

confidence: 89%

“…PCR-based prevalence studies have suggested that infection with BKV-II or -III is rare in all human populations worldwide (17,25). In contrast to these prior PCR-based prevalence studies, our serological analysis indicates that 33/48 (69%) members of this group of subjects are BKV-II seropositive (defined by EC 50 titers of 100 or greater).…”

Section: Resultscontrasting

confidence: 76%

BK Polyomavirus Genotypes Represent Distinct Serotypes with Distinct Entry Tropism

Pastrana

Ray

Magaldi

et al. 2013

J Virol

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“…BKV isolates can be grouped into four genetically distinct subspecies (genotypes) [20]–[22]. While chronic infection with BKV genotype I (BKV-I) is believed to be common almost to the point of ubiquity in all human populations worldwide, PCR-based studies suggest that BKV genotypes II, III, and IV only infect a minority of adults.…”

Section: Introductionmentioning

confidence: 99%

Neutralization Serotyping of BK Polyomavirus Infection in Kidney Transplant Recipients

et al. 2012

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BK polyomavirus (BKV or BKPyV) associated nephropathy affects up to 10% of kidney transplant recipients (KTRs). BKV isolates are categorized into four genotypes. It is currently unclear whether the four genotypes are also serotypes. To address this issue, we developed high-throughput serological assays based on antibody-mediated neutralization of BKV genotype I and IV reporter vectors (pseudoviruses). Neutralization-based testing of sera from mice immunized with BKV-I or BKV-IV virus-like particles (VLPs) or sera from naturally infected human subjects revealed that BKV-I specific serum antibodies are poorly neutralizing against BKV-IV and vice versa. The fact that BKV-I and BKV-IV are distinct serotypes was less evident in traditional VLP-based ELISAs. BKV-I and BKV-IV neutralization assays were used to examine BKV type-specific neutralizing antibody responses in KTRs at various time points after transplantation. At study entry, sera from 5% and 49% of KTRs showed no detectable neutralizing activity for BKV-I or BKV-IV neutralization, respectively. By one year after transplantation, all KTRs were neutralization seropositive for BKV-I, and 43% of the initially BKV-IV seronegative subjects showed evidence of acute seroconversion for BKV-IV neutralization. The results suggest a model in which BKV-IV-specific seroconversion reflects a de novo BKV-IV infection in KTRs who initially lack protective antibody responses capable of neutralizing genotype IV BKVs. If this model is correct, it suggests that pre-vaccinating prospective KTRs with a multivalent VLP-based vaccine against all BKV serotypes, or administration of BKV-neutralizing antibodies, might offer protection against graft loss or dysfunction due to BKV associated nephropathy.

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“…Second, there is limited knowledge with regard to how these DNA viruses evolve. For BKPyV, different subtypes of viral genomes have been demonstrated to evolve from distinct human populations, with the archetypal variants being the dominant circulating virus (10). The host cell factors that contribute to the molecular evolution of PyVs remain to be determined.…”

mentioning

confidence: 99%

Functional Upregulation of the DNA Cytosine Deaminase APOBEC3B by Polyomaviruses

Verhalen

Starrett

Harris

et al. 2016

J Virol

106

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The APOBEC3 family of DNA cytosine deaminases has important roles in innate immunity and cancer. It is unclear how DNA tumor viruses regulate these enzymes and how these interactions, in turn, impact the integrity of both the viral and cellular genomes. Polyomavirus (PyVs) are small DNA pathogens that contain oncogenic potentials. In this study, we examined the effects of PyV infection on APOBEC3 expression and activity. We demonstrate that APOBEC3B is specifically upregulated by BK polyomavirus (BKPyV) infection in primary kidney cells and that the upregulated enzyme is active. We further show that the BKPyV large T antigen, as well as large T antigens from related polyomaviruses, is alone capable of upregulating APOBEC3B expression and activity. Furthermore, we assessed the impact of A3B on productive BKPyV infection and viral genome evolution. Although the specific knockdown of APOBEC3B has little short-term effect on productive BKPyV infection, our informatics analyses indicate that the preferred target sequences of APOBEC3B are depleted in BKPyV genomes and that this motif underrepresentation is enriched on the nontranscribed stand of the viral genome, which is also the lagging strand during viral DNA replication. Our results suggest that PyV infection upregulates APOBEC3B activity to influence virus sequence composition over longer evolutionary periods. These findings also imply that the increased activity of APOBEC3B may contribute to PyV-mediated tumorigenesis. IMPORTANCEPolyomaviruses (PyVs) are a group of emerging pathogens that can cause severe diseases, including cancers in immunosuppressed individuals. Here we describe the finding that PyV infection specifically induces the innate immune DNA cytosine deaminase APOBEC3B. The induced APOBEC3B enzyme is fully functional and therefore may exert mutational effects on both viral and host cell DNA. We provide bioinformatic evidence that, consistent with this idea, BK polyomavirus genomes are depleted of APOBEC3B-preferred target motifs and enriched for the corresponding predicted reaction products. These data imply that the interplay between PyV infection and APOBEC proteins may have significant impact on both viral evolution and virusinduced tumorigenesis. P olyomaviruses (PyVs) are a family of small nonenveloped viruses containing an ϳ5-kb circular double-stranded DNA genome. Most human PyVs establish a subclinical persistent infection in healthy individuals (1). These viruses can reactivate under various immunosuppression conditions and cause a variety of severe diseases, including cancers (2). Among them, BK polyomavirus (BKPyV) reactivation is a major concern in kidney and bone marrow transplant patients due to the possibility of development of polyomavirus-associated nephropathy and hemorrhagic cystitis, respectively (3). Recently, there have also been increasing reports demonstrating an association between BKPyV infection and the occurrence of renourinary tumors (4). JC polyomavirus (JCPyV) reactivation can lead to progressive multifocal leu...

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Evolution of the BK polyomavirus: epidemiological, anthropological and clinical implications

Cited by 59 publications

References 84 publications

BK Polyomavirus Genotypes Represent Distinct Serotypes with Distinct Entry Tropism

BK Polyomavirus Genotypes Represent Distinct Serotypes with Distinct Entry Tropism

Neutralization Serotyping of BK Polyomavirus Infection in Kidney Transplant Recipients

Functional Upregulation of the DNA Cytosine Deaminase APOBEC3B by Polyomaviruses

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