JCPyV VP1 Mutations in Progressive Multifocal Leukoencephalopathy: Altering Tropism or Mediating Immune Evasion?

Abstract

Polyomaviruses are ubiquitous human pathogens that cause lifelong, asymptomatic infections in healthy individuals. Although these viruses are restrained by an intact immune system, immunocompromised individuals are at risk for developing severe diseases driven by resurgent viral replication. In particular, loss of immune control over JC polyomavirus can lead to the development of the demyelinating brain disease progressive multifocal leukoencephalopathy (PML). Viral isolates from PML patients frequently carry point mutations in the major capsid protein, VP1, which mediates virion binding to cellular glycan receptors. Because polyomaviruses are non-enveloped, VP1 is also the target of the host’s neutralizing antibody response. Thus, VP1 mutations could affect tropism and/or recognition by polyomavirus-specific antibodies. How these mutations predispose susceptible individuals to PML and other JCPyV-associated CNS diseases remains to be fully elucidated. Here, we review the current understanding of polyomavirus capsid mutations and their effects on viral tropism, immune evasion, and virulence.

Computational formulation of a multiepitope vaccine unveils an exceptional prophylactic candidate against Merkel cell polyomavirus

“…Using the NetCTL v1.2 server, unique CTL epitopes (9-mer) were predicted from the MCV-selected five antigenic proteins. A total of 90 (29,8,16, 21, and 16 CTL epitopes from the large T-antigen, small Tantigen, VP1, VP2, and VP3, respectively) unique epitopes were identified that were antigenic, immunogenic, non-toxic, and nonallergenic (Table S1). The best two CTL epitopes for each protein (total 10) were selected and considered for further evaluation (Table 3).…”

Progressive Multifocal Leukoencephalopathy

“…29 JCV-PML genetic variants frequently have point mutations in the VP1 region. 30 Point mutations in the VP1 gene cause conformational changes of the VP1 protein on the viral capsid and can alter binding ability and cellular tropism, possibly impeding viral neutralization and facilitating the infection of brain cells. 20,21,31 Host Genetics While predisposing conditions causing profound immune suppression are essential for developing symptomatic JCVassociated disease in most PML cases, only a small proportion of individuals at risk will develop it.…”

“…JCV-PML genetic variants frequently have point mutations in the VP1 region. 30 Point mutations in the VP1 gene cause conformational changes of the VP1 protein on the viral capsid and can alter binding ability and cellular tropism, possibly impeding viral neutralization and facilitating the infection of brain cells. 20,21,31…”

Polyomavirus Wakes Up and Chooses Neurovirulence

“…MuPyV also encodes for a precursor miRNA that is processed into two mature miRNAs, which coordinate the cleavage of early mRNA transcripts [ 24 ]. The capsids of both JCPyV and MuPyV are organized into 72 pentamers of VP1, and each pentamer is associated with either VP2 or VP3 [ 25 ]. The early and late regions are separated by a non-coding control region (NCCR), which contains the origin of replication and binding sites for host proteins that determine species and cell tropism [ 26 ].…”

“…Similarly, MuPyV resides persistently in the kidneys of infected mice [ 25 , 111 , 112 , 113 , 114 ]. Intracranial (IC) infection of MuPyV results in persistent viral DNA in the kidney [ 115 ].…”