Abstract
Progressive multifocal leukoencephalopathy (PML) is a severely debilitating and often fatal demyelinating disease of the central nervous system (CNS) in immunosuppressed individuals caused by JC polyomavirus (JCV), a ubiquitous human pathogen. Demyelination results from lytically infected oligodendrocytes, whose clearance is impaired in the setting of depressed JCV-specific T cell-mediated CNS surveillance. Although mutations in the viral capsid and genomic rearrangements in the viral non-coding region appear to set the stage for PML in the immunosuppressed population, mechanisms of demyelination and CNS antiviral immunity are poorly understood in large part due to absence of a tractable animal model that mimics PML neuropathology in humans. Early studies using mouse polyomavirus (MPyV) in T cell-deficient mice demonstrated productive viral replication in the CNS and demyelination; however, these findings were confounded by spinal cord compression by virus-induced vertebral bone tumors. Here, we review current literature regarding animal models of PML, focusing on current trends in antiviral T cell immunity in non-lymphoid organs, including the CNS. Advances in our understanding of polyomavirus lifecycles, viral and host determinants of persistent infection, and T cell-mediated immunity to viral infections in the CNS warrant revisiting polyomavirus CNS infection in the mouse as a bona fide animal model for JCV-PML.
Highlights
The human JC polyomavirus (JCV) persists silently in >50% of the healthy adult population, with recent evidence suggesting an even higher prevalence [1, 2]
Before the advent of highly active antiretroviral therapy (HAART), approximately 5% of individuals afflicted with HIV/AIDS developed progressive multifocal leukoencephalopathy (PML), such that PML became regarded as an AIDS-associated disease [11]
Progressive multifocal leukoencephalopathy, a rare complication of immunosuppression, is caused by infection of the central nervous system (CNS) by JC virus, a highly ubiquitous and silent human pathogen in healthy individuals. This wide discordance between virus prevalence and disease incidence appears to stem from the coalescence of multiple predisposing factors including viral determinants that alter host cell tropism, host immune determinants that affect CNS
Summary
The human JC polyomavirus (JCV) persists silently in >50% of the healthy adult population, with recent evidence suggesting an even higher prevalence [1, 2]. Immune reconstitution by HAART for AIDS or plasma exchange for monoclonal antibody therapy is the recommended treatment option for PML [23] Such regimens predispose patients to a rapid, robust, and often fatal influx of circulating leukocytes into the CNS termed immune reconstitution inflammatory syndrome (IRIS); paradoxically, these treatments can accentuate PML lesions, cause relapse of autoimmune disease or, in the case of organ transplant recipients, lead to graft rejection [24]. BKV isolates from kidney transplant patients with nephropathy and viremia had a high frequency of VP1 substitutions [34] These findings raise the possibility that VP1-specific neutralizing antibody responses select variant polyomaviruses with mutations in VP1 that enable escape from antiviral humoral immunity. Are there circumstances in which antiviral immune surveillance in the CNS may prove pathological rather than protective?
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