JC Virus Propagation is Potentiated by Glial Replication and Accelerated by Demyelination-Associated Glial Proliferation

Abstract

Progressive multifocal leukoencephalopathy (PML) is a demyelinating infection of the immunosuppressed brain, mediated by the gliotropic polyomavirus JCV. JCV replicates in human glial progenitor cells and astrocytes, which undergo viral T antigen-triggered mitosis, enabling viral replication. We asked if JCV spread might therefore be accelerated by glial proliferation. We found that dividing human astrocytes supported JCV propagation more than mitotically quiescent cells. Both bulk and single cell RNA-seq revealed that these JCV-infected glia exhibited cell cycle-linked perturbation of DNA damage response and transcriptional regulatory pathways. In vivo, JCV infection of humanized glial chimeras was greatly accentuated by cuprizone-induced demyelination and its associated mobilization of GPCs. Infection triggered the death of uninfected as well as infected glia in vivo, reflecting significant bystander death. These data suggest that demyelination-associated glial proliferation accelerates the spread of JCV, and argue for the aggressive prevention of new demyelinating events in patients at risk for PML.