BK Polyomavirus Genotypes Represent Distinct Serotypes with Distinct Entry Tropism

Abstract

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...

Naturally Occurring Capsid Protein Variants of Human Papillomavirus Genotype 31 Represent a Single L1 Serotype

“…The criterion used to designate serotypes is generally based upon a fold difference in antibody-mediated neutralization titers between viral types, which differ in magnitude and range between virus families: for adenovirus, 8-to 16-fold (52); for rotavirus, Ն20-fold (53); and for polyomavirus, 4-to 100-fold (54). For HPV there are no currently defined criteria with which to designate L1 serotypes.…”

Entry, infection, replication, and egress of human polyomaviruses: an update

“…BKPyV persists in the urinary tract of the individual and is shed in the urine asymptomatically. BKPyV exists in 4 genotypes (I-IV) and subtypes, which are distinguishable by neutralization serology (Pastrana et al 2013). Subtype Ia is thought to be the most prevalent subtype and is prevalent worldwide, and subtype IV is less common and its prevalence appears to vary in different world regions Jin 1993;Takasaka et al 2004).…”

“…Studies based on virus-like particle (VLP)-based neutralizing assays indicated that VP1 capsid proteins of each of the major BKPyV genotypes can reciprocally escape from neutralization by antibodies raised against the other types. These serotypedefining differences between the genotypes can be related to a few key amino acid differences within the VP1-BC2 surface loop (Pastrana et al 2013). Based on cellbased transduction assays, this study also indicated that different BKPyV genotypes and subtypes may have altered attachment requirements and virulence potential in vivo, reflecting the changes in amino acids within their VP1 capsomere knob (Pastrana et al 2013).…”

“…These serotypedefining differences between the genotypes can be related to a few key amino acid differences within the VP1-BC2 surface loop (Pastrana et al 2013). Based on cellbased transduction assays, this study also indicated that different BKPyV genotypes and subtypes may have altered attachment requirements and virulence potential in vivo, reflecting the changes in amino acids within their VP1 capsomere knob (Pastrana et al 2013). Komagome et al (2002) found through screening that the VLPs containing the JCPyV major viral capsid protein VP1 had the highest affinity for neoglycoproteins containing the terminal ␣2,6-linked sialic acid.…”

Virus Like Nanoparticles: Display Matters

“…Many viral surface antigens have the ability to selfassemble into VLPs that resemble the native viral particles in appearance, for example, in case of Human Papillomavirus (Kemp et al, 2011;Schiller and Muller, 2015), JC polyomavirus (Ray et al, 2015), BK polyomavirus (Pastrana et al, 2013) etc. Many others that cannot self-assemble, or those where the viral capsid is encased inside a lipid envelope, or those where the viral surface proteins are relatively mobile/ not rigid, can also potentially be displayed in a more rigid and thermodynamically stable fashion as synthetic VLPs.…”