title: The importance of mouse models to define immunovirologic determinants of progressive multifocal leukoencephalopathy.
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.
authors.affiliation: Immunology and Molecular Pathogenesis Graduate Program, Emory University , Atlanta, GA , USA.
authors.forename: Elizabeth L
authors.initials: EL
authors.lastname: Frost
authors.affiliation: Department of Microbiology and Immunology, The Pennsylvania State University College of Medicine , Hershey, PA , USA.
authors.forename: Aron E
authors.initials: AE
authors.lastname: Lukacher
keywords: JC virus; mouse model; natalizumab; polyomavirus; progressive multifocal leukoencephalopathy; tissue-resident memory T cells