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JC polyomavirus abundance and distribution in progressive multifocal leukoencephalopathy brain tissue implicates myelin sheath in intracerebral dissemination of infection

Wharton Jr, Keith and Quigley, Catherine and Themeles, Marian and Dunstan, Robert W. and Doyle, Kathryn and Cahir-McFarland, Ellen and Wei, Jing and Buko, Alex and Reid, Carl E. and Sun, Chao and Carmillo, Paul and Sur, Gargi and Carulli, John P. and Mansfield, Keith and Westmoreland, Susan V. and Staugaitis, Susan M. and Fox, Robert J. and Meier, Werner and Goelz, Susan (2016) JC polyomavirus abundance and distribution in progressive multifocal leukoencephalopathy brain tissue implicates myelin sheath in intracerebral dissemination of infection. PLoS One.

Abstract

Over half of adults are seropositive for JC polyomavirus (JCV), but rare individuals develop progressive multifocal leukoencephalopathy (PML), a demyelinating JCV infection of the central nervous system. Previously, PML was primarily seen in immunosuppressed patients with AIDS or certain cancers, but it has recently emerged as a drug safety issue through its association with diverse immunomodulatory therapies. To better understand the relationship between the JCV life cycle and PML pathology, we studied brain tissue from a 70-year-old psoriasis patient on efalizumab following a ~2 month course of PML. Sequence analysis of lesional brain tissue identified PML-associated viral mutations in regulatory (non-coding control region) DNA, capsid protein VP1, and the regulatory angoprotein, as well as novel mutations in capsid protein VP2, indicating rampant viral evolution. Nine samples, including three gross PML lesions and normal-appearing adjacent tissue, were characterized by histopathology and subject to quantitative genomic, proteomic, and immunohistochemical analyses. We observed a striking correlation between the spatial extent of demyelination, axonal destruction, and dispersion of JCV along white matter myelin sheath. Our observations in this case, as well as in a case of PML-like disease in an immunocompromised rhesus macaque, suggest that long-range spread of polyomavirus and axonal destruction in PML might involve extracellular association between virus and the white matter myelin sheath.

Item Type: Article
Date Deposited: 18 May 2016 23:45
Last Modified: 18 May 2016 23:45
URI: https://oak.novartis.com/id/eprint/27522

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