Human glial chimeric mice reveal astrocytic dependence of JC virus infection
Yoichi Kondo, … , Leonid Gorelik, Steven A. Goldman
Yoichi Kondo, … , Leonid Gorelik, Steven A. Goldman
Published November 17, 2014
Citation Information: J Clin Invest. 2014;124(12):5323-5336. https://doi.org/10.1172/JCI76629.
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Research Article

Human glial chimeric mice reveal astrocytic dependence of JC virus infection

Abstract

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 immunodeficient and myelin-deficient mice. Intracerebral delivery of JCV resulted in infection and subsequent demyelination of these chimeric 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 T antigens and exhibited apoptotic death. Engraftment of human GPCs in normally myelinated and immunodeficient mice resulted in humanized white matter that was chimeric for 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 T antigen–triggered oligodendroglial apoptosis. More broadly, this study provides a model by which to further assess the biology and treatment of human-specific gliotropic viruses.

Authors

Yoichi Kondo, Martha S. Windrem, Lisa Zou, Devin Chandler-Militello, Steven J. Schanz, Romane M. Auvergne, Sarah J. Betstadt, Amy R. Harrington, Mahlon Johnson, Alexander Kazarov, Leonid Gorelik, Steven A. Goldman

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Figure 1

Human astroglia are most efficiently infected by JCV in vitro.

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Human astroglia are most efficiently infected by JCV in vitro. Human GPC...
Human GPCs and astrocytes were readily infected by JCV in vitro, with robust expression within days of both the early viral large T-Ag and the later VP1 capsid protein. (A) Both T-Ag and VP1 were expressed by CD140a+ GPCs grown in suspension culture, and both were more abundantly expressed at 10 DPI than at 3 DPI. (B) In CD44-sorted GFAP+ astrocytes, T-Ag was expressed as early as 1 DPI, whereas VP1 was first expressed at 3 DPI. (C) In contrast, O4+ oligodendrocyte infection in vitro was both delayed and of relatively low efficiency, showing weak T-Ag expression without VP1 at 5 DPI (arrowheads), with VP1+ oligodendroglia (arrows) appearing only at 10 DPI. (D) Representative images of a JCV-infected T-Ag+VP1+ oligodendrocyte at 10 DPI; nuclear hypertrophy (arrows) was apparent. (E) At 3 and 5 DPI, T-Ag+ oligodendroglial infection was of significantly lower efficiency than that of astrocytes, while oligodendrocytic VP1+ JCV replication was even less frequent. By 10 DPI, VP1+ oligodendroglia as well as astrocytes began to accumulate. Data are presented as percentage of cells of each phenotype at 3, 5, and 10 DPI. Scale bars: 20 μm. *P < 0.05; ***P < 0.01.