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Published in final edited form as: Rev Med Virol. 2020 Mar 3;30(4):e2102. doi: 10.1002/rmv.2102

BK polyomavirus diversity—Why viral variation matters

Jason T Blackard 1, Stella M Davies 2, Benjamin L Laskin 3
PMCID: PMC7363569  NIHMSID: NIHMS1579126  PMID: 32128960

Summary

BK polyomavirus (BKPyV or BKV) is a non-enveloped, circular double-stranded DNA virus that may exceed 80% seroprevalence in adults. BKV infection typically occurs during childhood, and the majority of adults are latently infected. While BKV infection is rarely associated with clinical disease in most individuals, in immunosuppressed individuals, reactivation may cause kidney (BK-associated nephropathy) or bladder (hemorrhagic cystitis and ureteral stenosis) injury. No antiviral therapies have been approved for the treatment of BKV infection. Reducing immunosuppression is the most effective therapy, although this is not feasible in many patients. Thus, a robust understanding of viral pathogenesis and viral diversity remains important for the development of future therapeutic strategies. Studies of BKV diversity are quite sparse compared to other common viral infections; thus, much of our understanding of BVK variability and evolution relies heavily analogous studies of other viruses such as HIV or viral hepatitis. We provide a comprehensive review of BKV diversity at the population and individual level with careful consideration of how viral variability may impact viral replication, pathogenesis, tropism, and protein function. We also discuss a number of outstanding questions related to BK virus diversity that should be explored rigorously in future studies.

Keywords: BK polyomavirus, BK virus, diversity, variation, evolution

1 |. INTRODUCTION

BK polyomavirus (BKPyV or BKV) was first isolated from the urine of a kidney transplant recipient in 1971. BKV belongs to the Polyomaviridae family of non-enveloped, circular double-stranded DNA viruses that is ~5000 nucleotides in length.1,2 Human polyomaviruses are thought to be transmitted through direct person-to-person contact and via contaminated surfaces, food, and water, although confirmation of these transmission routes is difficult due to the asymptomatic nature of primary infections and/or clinically non-specific (eg, flu-like) presentations.3 BKV infection typically occurs during childhood, and the majority of adults are latently infected, with the virus remaining dormant in the epithelial cells of the kidney and bladder in immunocompetent persons. Depending upon the study population, the seroprevalence of BKV may exceed 80% in adults.4 While BKV infection in most individuals is rarely associated with clinical disease, in immunosuppressed individuals, reactivation may cause kidney (BK-associated nephropathy) or bladder (hemorrhagic cystitis and ureteral stenosis) injury. More rarely, BKV is associated with progressive multifocal leukoencephalopathy meningitis and encephalitis, retinitis, pneumonitis, prostate cancer, and HIV-associated salivary gland disease renal carcinoma.5

BKV encodes multiple regulatory regions and structural proteins (VP1, VP2, and VP3). VP1 is the major capsid protein of virions and accounts for ~80% of their protein content. The non-coding control region (NCCR) of ~400 nucleotides contains the origin of replication and regulatory sequences for early and late transcription.5 A number of transcription factor binding sites exist within the NCCR and serve as determinants of host cell tropism. An excellent review of BKV biology has been published previously by Helle et al.6 No antiviral therapies have been approved for the treatment of BKV infection. Therefore, lowering of immunosuppression is the most effective therapy, although this is not feasible in many patients. Thus, a robust understanding of viral pathogenesis and viral diversity remains important for the development of future therapeutic strategies.

2 |. VIRUS DIVERSITY IS CLINICALLY RELEVANT

Studies of BKV diversity are quite sparse compared to other common viral infections such as HIV, hepatitis B virus (HBV), or hepatitis C virus (HCV) (see Figure S1 for the annual number of publications from 1987 to 2019). However, understanding how viral diversity impacts these exemplar infections is informative for designing future studies of BKV diversity. For example, viral variation is a defining feature of HIV disease. Within an individual, HIV exists as a population of related yet distinct viral variants termed the viral quasispecies that permits rapid, adaptive responses to immunologic selection pressures, antiviral therapies, and/or the cellular microenvironment, thereby contributing to viral fitness.7 Minor viral mutations can significantly alter key biological properties, including cellular tropism, co-receptor utilization, drug resistance, neutralization properties, and transactivation. The HIV long-terminal repeats (LTRs) contain cis-acting sequences that are recognized by viral and cellular proteins and regulate viral gene expression. The LTR exhibits diversity at the population and individual levels, and minor changes within an LTR can have significant effects on replication kinetics, cell tropism, transmission, and disease progression.8–24 Similarly, it is well established that variability within the HIV env and pol genes contribute to cell tropism, pathogenesis, replicative fitness, and/or drug resistance.

Viral diversity occurs during HCV infection, and the HCV quasispecies is a key determinant of replication capacity or fitness, cell tropism, immunologic escape, and antiviral drug resistance.25–39 Importantly, resistance associated mutations are relatively common during HCV infection and compromise treatment outcomes, while numerous studies have identified key positions within the HCV polymerase that reduce or enhance viral replication in vitro.40–53 Such polymorphisms can lead to rapid resistance and impact HCV replication and viral fitness in the absence of antiviral agents.

Analysis of complete HBV genomes has demonstrated the existence of multiple genotypes that influence chronicity, disease severity, and antiviral response rates.54,55 Moreover, the HBV mutation rate is relatively high due to the low fidelity of the viral reverse transcriptase,56 and HBV also exists as a viral quasispecies within an infected individual. This heterogeneity facilitates rapid, adaptive changes in response to immune selection pressure and antiviral therapy and has consequences for viral persistence and HBV-associated disease.57 Mutations within all HBV open reading frames may impact HBsAg expression, viral detection, vaccine escape, and/or HBV replication.

Given the central role of diversity to many common viral pathogens, robust evaluation of BKV diversity is essential for understanding the varied course of clinical disease.58,59 A number of investigators have suggested that cell determinants of BKV infection, such as cellular receptors and cell type-specific transcription can regulate viral infection and expression and contribute to differences in cell tropism between different BKV isolates.58 As reviewed by Moens and Van Ghelue,58 multiple amino acid substitutions have been described in the VP1, large T antigen, and agnoprotein; however, biological characterization of these mutations has rarely been performed. Similarly, the landscape of the NCCR, as well as polymorphisms within viral coding regions, may impact cell permissiveness of BKV isolates. BK virus diversity will almost certainly facilitate drug resistance if BK virus-specific therapies are developed in the future.

3 |. BKV SUBTYPES/SUBGROUPS

Prior to 1993, BKV strains worldwide were classified using a serological method.60 In 1993, Jin et al PCR amplified and sequenced a 287 base pair (bp) region of the VP1 gene - designated the 287-bp typing region - that provided evidence of distinct BKV genotypes.61 Based on a relatively small number of full-length BKV genomes currently available, it is now appreciated that BKV consists of antigenically distinct serotypes and multiple subtypes (I-IV)62,63 as shown in Figure 1. Notably, BK isolates from distinct individuals are rarely identical, suggesting adaptation of BK viral sequences to the unique immunologic environment of their host. Subtype I is the most common worldwide, followed by subtype IV. Subtype I can be divided further into subgroups Ia, Ib, and Ic based on nucleotide similarity. Subtype II is rare and has limited sequence data available for analysis. Additionally, subtypes II, III, and IV, along with subgroups Ib1 and Ib1, function as five fully distinct serotypes.64 Unfortunately, BKV genotyping studies have not been conducted in most countries, and it is unclear if the published reports are representative of the BK subtypes circulating in that region. Thus, the true geographic distribution of these subtypes is not fully appreciated and requires further investigation. For example, in the United States, BKV seropositivity rates are >85% in adults,65 and all subtypes have been detected although not in equal proportions, as shown in Table 1.63,66–70 Further study in larger cohorts and distinct at-risk populations should provide a more accurate assessment of the circulating BKV subtypes and their relative proportion.

FIGURE 1.

FIGURE 1

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Full-length BK genomes were downloaded from GenBank. For individuals with multiple sequences available, a single representative sequence was chosen for inclusion. 258 sequences were evaluated using a Bayesian inference approach as implemented in the BEAST v1.10.1 software and are labeled using their GenBank accession number and country of origin. Blue sequences belong to BK subtype I, green sequences to subtypes II/III, and red sequences to subtype IV

TABLE 1.

The distribution of BKV subtypes in the United States

BK subtype
References Sample number I II III IV
Sahoo66 18 17 1
Chen67 3 3
Luo68 21 15 5 1
Zhong69 67 55 3 9
Kapusinszky70 1 1
Total 110 90 (81.8%) 8 (7.3%) 2 (1.8%) 10 (9.1%)
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It is important to note that BKV diversity is influenced by a variety of selection pressures including the adaptive immune response, co-infections, and immunosuppressive and/or antiviral agents. Thus, BKV sequences within unrelated individuals (ie, no evidence of epidemiologic linkage) are rarely identical. For example, Krumbholz et al evaluated within subtype/subgroup and intersubtype/subgroup variability of 92 unique full-length BKV sequences.71 Between subtype I subgroups and between subtypes (I–IV), the mean genetic distances ranged from 1.06% to 5.5%, while intrasubtype/intrasubgroup genetic distances were lower at 0.18% to 0.47%. These data demonstrate that careful consider of the viral quasispecies may impact a variety of clinically relevant outcomes such as diagnosis of infection, viral replication, immune response, disease outcome, and treatment response.

It has been suggested that a particular BKV subtype may have greater potential to cause clinical disease compared to other subtypes.72 Bauer et al found that a single amino acid substitution within VP1 can affect binding of a mouse polyomavirus to its receptor and shorten the time to lethality by more than 3-fold,73 although detailed studies of BK virus interactions with its receptor(s) remain uncommon. A recent study suggests that BKV genotypes may differ in cellular entry tropism and pathogenic potential.64 Using reporter pseudoviruses, Pastrana et al demonstrated that BKV I, II, III, and IV are distinct serotypes and that BKV subgenotypes Ib1 and Ib2 also represent distinct serotypes.64 These differences map to a hypervariable region including residues 61 to 82 of the VP1. Another study found that distinct BKV isolates representing subtypes I, II, III, and IV replicated at different rates in the same cell type.74 Sequence variability within the transcription factor binding sites in the canonical NCCR exist and may contribute to virus reactivation, replication, and pathogenesis.59,75–81 Polyomavirus NCCRs differ in length, sequence, and organization, and basal NCCR activity depends on the activation state of the host cell type.59 A number of BKV NCCR variants have been reported, although few have been evaluated for their ability to alter replication. Olsen et al replaced the NCCR of the Dunlop isolate of BKV with several NCCRs from urine or kidney allograph biopsies and noted considerable variation in replication efficiency in vitro, suggesting that NCCR variability does impact replication rate.77

Studies have also demonstrated functional differences amongst BK genotypes/subgroups. For example, subtype I isolates grow more efficiently in human renal epithelial cells compared to subtype IV isolates.82 In renal transplant recipients, urine viral loads were higher for individuals infected with BK genotype Ia compared to Ib1.83 Genotype Ia was also associated with positive immune selection pressure at VP1 loops, which was absent in genotype Ib1 sequences. However, this has not been investigated further with other BK genotypes/subgroups or in other geographic regions. Virulence determinants also reside within VP1; therefore, mutations within this region may alter receptor specificity or other phenotypic properties of BKV.73,84 For example, of 500+ complete VP1 genes currently available in GenBank, a number of unique amino acid sequences are presented as shown in Figure 2. Whether these distinct viral sequences represent VP1s with divergent functions/genotypes remains to be evaluated in vitro. An interlaboratory collaboration in France reported that polymorphisms within regions targeted by PCR primers during BK viral load assays were a major source of variability.85 Thus, accurate measures of BK viremia may be challenging until BKV diversity is carefully considered during primer design and evaluation.

FIGURE 2.

FIGURE 2

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532 complete VP1 genes were downloaded from GenBank and aligned. Duplicate sequences were removed, and the resulting dataset is shown as a WebLogo with the height of each amino acid representing its relative proportion at that position of VP1

4 |. INTRAPATIENT BKV DIVERSITY

It was recently reported that BKV has the highest mutation rate for double-stranded DNA viruses - one that is similar to single-stranded RNA viruses.86 Yet, only a very limited number of studies have examined BKV diversity within an individual. Chen et al67 studied one patient with HIV, one with Capillary Leak Syndrome, and one healthy control from the United States/West Africa. Takasaka et al87 studies six renal transplant recipients from Japan. Kapusinszky et al70 studied one pediatric renal transplant patient with nephropathy from the United States. Data from these three studies were reconstructed using a Bayesian inference approach and colored by their patient of origin as shown in Figure 3. Chen et al found that full-length viral sequences from BKV cases formed monophyletic clusters of related yet distinct viral variants - termed the viral quasispecies and that the NCCR has unique nucleotide differences within each variant.67 Similarly, Takasaka et al evaluated full-length genomes from renal transplant patients with the four of six having multiple viral variants detected.87 Analysis of VP1 sequences found BK viral variants in 25 of 25 individuals evaluated.68 Compared to healthy controls, BK viremia/nephropathy was characterized by altered sequence complexity and immune selection pressure. Quasispecies variability also exists within the NCCR.76 The quasispecies evolves over time and may impact replication.87–89 A recent study reported that intrapatient variation also modified the specific receptor glycans that were engaged by BKV during host cell entry.89 Moreover, next generation sequencing of full-length BKV genomes identified an average of 110 polymorphisms per sample.86 Amongst all amino acid positions, 37.9% were polymorphic in the agnoprotein, 12.4% in VP1, 10.0% in VP2, 11.2% in VP3, 8.2% in the LTA, and 8.7% in STA.

FIGURE 3.

FIGURE 3

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Full-length genomes from three studies of BK quasispecies diversity were downloaded from GenBank. Chen et al.67 studied one patient with HIV, one with Capillary Leak Syndrome, and one healthy control from the United States/West Africa. Takasaka et al.87 studied six renal transplant recipients from Japan. Kapusinszky et al.70 studied one pediatric renal transplant patient with nephropathy from the United States. Sequences were evaluated using a Bayesian inference approach labeled using their GenBank accession number and country of origin. Sequences are colored by their patient of origin

Infection with multiple BK viruses is also common, occurring in 12 of 25 individuals in one study.68 Similarly, Jin et al found dual infections with more than one subtype in HIV-infected patients, children, and pregnant women but not in bone marrow recipients.90 Recombination represents another important driver of viral evolution and has been observed within the BKV VP1.68 However, large, population-based studies of BKV dual infection and recombination have not been performed to date. Moreover, complementation can rescue non-functional BK variants91 highlighting the potential importance of recombination. BKV may exhibit distinct subtypes in the urine vs plasma suggesting tissue-specific selection pressures and viral compartmentalization.92

5 |. FUTURE DIRECTIONS

Multiple nucleotides and amino acid residues are known to impact BK virus replication, pathogenesis, tropism, and protein function. These include amino acids that regulate viral entry, replication, and/or assembly, multiple structural protein modifications, nuclear localization signals, amino acids responsible for transformation, transcription factor binding sites, T cell epitopes, and viral motifs that permit interactions with cellular proteins.5,6,66,93–103 BKV also contains a microRNA (BKPyV-3p-miRNA) that targets large T-antigen transcripts, thereby downregulating viral replication.79,104–110 Collectively, these data imply that a number of outstanding questions related to BK virus diversity remain to be explored in depth, including:

  1. Is BKV subtype/subgroup associated with specific disease presentations such as hemorrhagic cystitis after hematopoietic cell transplantation and/or BKV-associated nephropathy after hematopoietic or solid organ transplantation? This question is best answered in large cohort studies in which multiple BKV subtypes are circulating and disease outcomes are carefully monitored. Over-representation of a particular BKV subtype/subgroup in certain at-risk and/or disease-specific populations would then provide preliminary evidence of distinct pathogenesis associated with different BKV subtypes/subgroups.

  2. Are there specific viral mutations associated with altered BKV DNA levels? Based on our current understanding of viral pathogens, it is quite reasonable to suspect that BKV polymorphisms impact the overall function of viral proteins and/or their interactions with the host’s immune system. This hypothesis can be evaluated by rigorous phylogenetic and signature pattern analysis of viral sequences from individuals with high BKV viremia or viruria vs individuals with low BKV viremia or viruria, although potential confounders such as age, race, gender, BKV subtype/subgroup, use of immunosuppressive agents, and/or the presence of other co-infections must be considered.

  3. Are there specific viral mutations associated with the presence of BKV in the plasma? While detection of BKD in the plasma is less common than detection in the urine, it is important to evaluate whether the viruses circulating in both compartments are identical or represent viruses that are uniquely adapted for replication within a particular cell type or tissue.

  4. Similarly, are there specific viral mutations that are associated with the presence/absence of BKV aggregates in the urine - referred to as Haufen particles - which are sensitive and specific for biopsyproven BK nephropathy111,112?

  5. Is BKV diversity correlated with absolute lymphocyte count? There are data suggesting that BKV DNA levels are elevated when CD4 T cell counts are less than 200 cells/mm3.113–115 However, the impact of immunosuppression - and distinct types of immunosuppression - on BKV diversity has rarely been evaluated.84

  6. Does diversity within BKV proteins predict ELISPOT response to BKV infection and/or reactivation? BKV-specific immune responses may control BKV replication and reactivation; thus, viral diversity within key immunologic epitopes may also impact viral replication and reactivation.66,102,116,117 This is of significant clinical interest and requires robust evaluation of BKV-specific immune responses and the presence/absence of BKV epitope diversity in well-characterized clinical cohorts.

  7. Does BKV diversity change in response to immunosuppression and is this dependent upon the specific immunosuppressive strategy utilized?

  8. How does BKV diversity impact the development of a successful immunization strategy?

  9. Does BKV diversity impact the detection of seropositive transplant donors and recipients? With other DNA viruses such as CMV and EBV, risk of post-transplant infection is related to donor and recipient serostatus mismatching. Similar data on the risk of BK virus infection related to donor or recipient serostatus are less available. As BK serological assays become more widely used in clinical practice, it will be important to understand if BK diversity will influence these measurements and the associated clinical relevance.

6 |. CONCLUSIONS

Understanding viral diversity has led to improved clinical outcomes for patients with HIV, HBV, and HCV. Our knowledge of the associations between BK virus diversity and clinical disease is much less compared to these other well-studied viral infections. The significance of learning about viral diversity will be greater as new therapeutic strategies for BK emerge. For example, novel treatments, such as the infusion of third party or donor-derived virus-specific T cells (VSTs), have shown promise in the treatment of refractory viral infections in immunosuppressed patients. However, manufacturing VSTs is a time and resource intensive process, and not all centers can provide such therapies to all of their patients in need. Therefore, understanding viral diversity may provide for the identification of the patients at highest risk of disease, allowing for the rational targeting of therapy to the patients who are likely to derive the most benefit.

Supplementary Material

supplemental figure

ACKNOWLEDGEMENTS

Dr. Laskin is supported by the National Institute of Diabetes and Digestive and Kidney Diseases through grant K23 DK101600. Dr. Davies is supported by the Eunice Kennedy Shriver National Institute of Child Health and Human Development under award number R01 HD093773.

Funding information

Eunice Kennedy Shriver National Institute of Child Health and Human Development, Grant/Award Numbers: HD093773, R01; National Institute of Diabetes and Digestive and Kidney Diseases, Grant/Award Number: K23 DK101600

Footnotes

CONFLICT OF INTEREST

The authors have no conflicts of interest to report.

SUPPORTING INFORMATION

Additional supporting information may be found online in the Supporting Information section at the end of this article.

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