Modeling JCV virus infection

Kondo Y, Windrem MS, Zou L, Chandler-Militello D, Schanz SJ, Auvergne RM, Betstadt SJ, Harrington AR, Johnson M, Kazarov A, Gorelik L, Goldman SA.Human glial chimeric mice reveal astrocytic dependence of JC virus infection. J Clin Invest. 2014 Nov . pii: 76629. doi: 10.1172/JCI76629. [Epub ahead of print]

Progressive multifocal leukoencephalopathy (PML) is a demyelinating disease triggered by infection with the human gliotropic JC virus (JCV). Due to the human-selective nature of the virus, there are no animal models available to investigate JCV pathogenesis. To address this issue, we developed mice with humanized white matter by engrafting human glial progenitor cells (GPCs) into neonatal (post-birth) immunodeficient (no effective immune system so it will not reject human cells) and myelin-deficient mice. The human cells then produce the myelin in the miceIntracerebral delivery (brain injection) of JCV resulted in infection and subsequent demyelination of these mice. Human GPCs and astrocytes were infected more readily than oligodendrocytes, and viral replication was noted primarily in human astrocytes and GPCs rather than oligodendrocytes, which instead expressed early viral antigens and exhibited death. Engraftment of human GPCs in normally myelinated and immunodeficient mice resulted in humanized white matter that had human astrocytes and GPCs. JCV effectively propagated in these mice, which indicates that astroglial infection is sufficient for JCV spread. Sequencing revealed progressive mutation of the JCV capsid protein VP1 after infection, suggesting that PML may evolve with active infection. These results indicate that the principal CNS targets for JCV infection are astrocytes and GPCs and that infection is associated with progressive mutation, while demyelination is a secondary occurrence, following oligodendroglial apoptosis. More broadly, this study provides a model by which to further assess the biology and treatment of human-specific gliotropic viruses.
Demyelination after JC virus has been mooted as a main problem in PML, however in this study they got a mouse and made it contain human glial cells and mylein and it suggests that infection of astrocytes is the main problem and that oligodendrocyte is a later casualty. This now gives a tool to hunt for treatments to JCV infection

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