JC virus propagation is potentiated by glial replication and accelerated by demyelination-associated glial proliferation

Progressive multifocal leukoencephalopathy (PML) is a demyelinating infection of the brain of immunosuppressed individuals, mediated by the gliotropic polyomavirus JCV. JCV replicates in mitotically-competent human glial progenitor cells and astrocytes, which are triggered to divide in the setting of viral T antigen-mediated cell cycle entry, allowing viral replication; the death of mitotically-incompetent oligodendrocytes occurs secondarily, largely through T antigen-mediated apoptosis. This observation suggested that JCV infection might be potentiated by astrocytic replication, and hence accelerated in the setting of mitotic gliogenesis. To test this hypothesis, we tagged dividing human glia in vitro with bromodeoxyuridine (BrdU), then infected them with JCV MAD1, and confirmed that proliferating human astrocytes are more supportive of JCV propagation than mitotically quiescent cells. In vitro, scratch assays confirmed that viral propagation was greatly enhanced in peri-scratch regions of dividing glia. JCV infection of human glial chimeras established that infection was greatly accentuated by cuprizone-mediated demyelination, which was associated with increased glial progenitor cell proliferation. JCV infection in vivo was associated with caspase3-defined death of uninfected as well as infected oligodendrocytes, suggesting the contribution of bystander death to JCV-associated demyelination. These results suggest that JCV propagation in PML may be potentiated by glial cell division, and that the accentuated glial cell division and hence DNA replication attending acute demyelination might provide an especially favorable environment for JCV propagation and PML progression. These data thus argue for the aggressive prevention of new demyelinating events in patients at risk for PML.