The human polyomaviruses, BK virus and JC virus, have long been associated with serious diseases including polyomavirus nephropathy and progressive multifocal leukoencephalopathy. Both viruses establish ubiquitous, persistent infections in healthy individuals. Reactivation can occur when the immune system is impaired, leading to disease progression. Recently, the human polyomavirus family has expanded with the identification of three new viruses (KI, WU and Merkel cell polyomavirus), all of which may prove to be involved in human disease. This review describes the general aspects of human polyomavirus infections and pathogenicity. Current topics of investigation and future directions in the field are also discussed.
BK virus (BKV) is a nonenveloped, ubiquitous human polyomavirus that establishes a persistent infection in healthy individuals. It can be reactivated, however, in immunosuppressed patients and cause severe diseases, including polyomavirus nephropathy. The entry and disassembly mechanisms of BKV are not well defined. In this report, we characterized several early events during BKV infection in primary human renal proximal tubule epithelial (RPTE) cells, which are natural host cells for BKV. Our results demonstrate that BKV infection in RPTE cells involves an acidic environment relatively early during entry, followed by transport along the microtubule network to reach the endoplasmic reticulum (ER). A distinct disulfide bond isomerization and cleavage pattern of the major capsid protein VP1 was observed, which was also influenced by alterations in pH and disruption of trafficking to the ER. A dominant negative form of Derlin-1, an ER protein required for retro-translocation of certain misfolded proteins, inhibited BKV infection. Consistent with this, we detected an interaction between Derlin-1 and VP1. Finally, we show that proteasome function is also linked to BKV infection and capsid rearrangement. These results indicate that BKV early entry and disassembly are highly regulated processes involving multiple cellular components.BK virus (BKV) is a member of the Polyomaviridae family, which also includes the well-studied simian virus 40 (SV40) and human JC virus (JCV) (21). Like other members of this family, BKV has a small (40 to 45 nm in diameter), nonenveloped, icosahedral capsid that contains an ϳ5-kb circular double-stranded DNA genome (5). BKV infection is ubiquitous in the human population and occurs during early childhood (24). Primary infection with BKV is followed by dissemination to the kidney and urinary tract, in particular to kidney tubule epithelial cells and urinary tract epithelial cells, where the virus establishes a lifelong persistent infection (9). This infection remains asymptomatic in immunocompetent individuals, but under conditions of immunosuppression, BKV can undergo reactivation resulting in viral shedding in the urine and may eventually lead to severe diseases, such as polyomavirus nephropathy in renal transplant patients and hemorrhagic cystitis in bone marrow transplant recipients (2). The incidence of BKV-related disease has greatly increased recently due to the introduction of new and more potent immunosuppressive agents and the increase in the number of transplants performed (21). No specific antiviral drugs for BKV infection are currently available, and the most common approach to control BKV reactivation is to reduce the immunosuppression, which might leave patients at risk for graft rejection (53). In addition, the immune components that are involved in controlling BKV persistence and reactivation are not well defined. Therefore, a better understanding of the BKV life cycle is warranted to aid in the design of novel, more-efficient antiviral strategies.Based on cryo-electron mic...
BK virus (BKV) is a polyomavirus that ubiquitously infects the human population. Following a typically subclinical primary infection, BKV establishes a lifelong persistent infection in the kidney and urinary tract. BKV is known to reactivate and cause severe disease in immunosuppressed patients, particularly renal and bone marrow transplant patients. Infection of BKV in rodent animal models or cells in culture often results in tumor formation or transformation, respectively. When co-expressed with activated oncogenes, BKV large tumor antigen drives the transformation of primary human cells. An etiological role of BKV in human cancer, however, remains controversial. Multiple reports have demonstrated conflicting results in regards to the presence of BKV sequences and/or proteins in various tumor types. This review compiles the most recent findings of BKV detection in a number of human cancers. Due to the lack of conclusive causality data from these studies, there does not appear to be a definitive association between BKV and human cancers.
Polyomavirus nephropathy (PVN) results in renal dysfunction and graft loss in up to 10% of all kidney transplant recipients (18). It is widely accepted that BK virus (BKV) is the etiological agent responsible for the majority of cases of PVN, which are typically diagnosed within the first year after transplantation (19,20). PVN is characterized by the lytic, destructive replication of BKV in proximal tubule epithelial cells in the transplanted kidney and is normally diagnosed by renal biopsy to assess histological effects of infection, PCR to determine viral presence and loads in the urine and blood, and the detection of decoy cells, which are cells with distinct intranuclear inclusion bodies that are shed during active BKV replication, in the urine (reviewed in references 10, 17, and 30). Since there are currently no effective antiviral treatments for BKV infection, the most common approach used to control PVN is to decrease the patient's immunosuppressive regimen. However, such an approach increases the risk of graft rejection and thus is not an appealing strategy. The prevalence of PVN is increasing with the advent of new, more powerful immunosuppressive therapies, making it a growing concern for the transplant community.The human polyomavirus BKV was first isolated in 1971 in the urine of a renal transplant recipient (11). BKV virions are small (40 to 45 nm in diameter), nonenveloped, and icosahedral and contain a circular, double-stranded DNA genome of approximately 5.2 kb (reviewed in reference 29) which is associated with cellular histones to form a chromatin-like structure (28). The genome encodes only six known proteins: the early proteins, large tumor antigen (TAg) and small tumor antigen, and the late proteins, VP1, VP2, VP3, and agnoprotein. BKV infects nearly the entire population, with seroprevalence reaching 60 to 80% by the age of 10 (reviewed in reference 23). BKV is thought to be contracted by respiratory transmission, and the primary infection is typically subclinical. Following the initial infection, BKV spreads to other cells of the body, most notably peripheral blood mononuclear cells (9) and cells of the kidney and urinary tract (4,16,39), in which the virus establishes a persistent, subclinical infection. It is at these sites in immunocompromised patients that BKV reactivates to a lytic infection, resulting in BKV-associated diseases, such as PVN.Previously, we described an in vitro system that allows the study of BKV lytic infection of primary human proximal tubule epithelial cells (27). The functions of proximal tubule cells in the kidney include facilitation of the recovery of blood products, maintenance of blood pressure and volume, and production and release of cytokines and chemokines to communicate with the host immune system (2, 6). Proximal tubule cells remain in a differentiated state for up to six passages in tissue culture (21) and thus provide an environment similar to that which BKV encounters in an immunocompromised host. By introducing individual elements of the immune sys...
Graphical Abstract Highlights d Latent polyomavirus infections generate a potent, neutralizing antibody response d The anti-BKV repertoire is clonally diverse and harbors crossreactive antibodies d Memory IgM B cell receptors are affinity matured and isotype restricted d A monoclonal cross-neutralizing IgG binds a conserved quaternary viral epitope SUMMARY Human polyomaviruses cause a common childhood infection worldwide and typically elicit a neutralizing antibody and cellular immune response, while establishing a dormant infection in the kidney with minimal clinical manifestations. However, viral reactivation can cause severe pathology in immunocompromised individuals. We developed a high-throughput, functional antibody screen to examine the humoral response to BK polyomavirus. This approach enabled the isolation of antibodies from all peripheral B cell subsets and revealed the anti-BK virus antibody repertoire as clonally complex with respect to immunoglobulin sequences and isotypes (both IgM and IgG), including a high frequency of monoclonal antibodies that broadly neutralize BK virus subtypes and the related JC polyomavirus. Cryo-electron microscopy of a broadly neutralizing IgG single-chain variable fragment complexed with BK virus-like particles revealed the quaternary nature of a conserved viral epitope at the junction between capsid pentamers. These features unravel a potent modality for inhibiting polyomavirus infection in kidney transplant recipients and other immunocompromised patients.
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