JC Polyomavirus Abundance and Distribution in Progressive Multifocal Leukoencephalopathy (PML) Brain Tissue Implicates Myelin Sheath in Intracerebral Dissemination of Infection

• Published in: PloS one Vol. 11; no. 5; p. e0155897
• Main Authors: Wharton, Jr, Keith A, Quigley, Catherine, Themeles, Marian, Dunstan, Robert W, Doyle, Kathryn, Cahir-McFarland, Ellen, Wei, Jing, Buko, Alex, Reid, Carl E, Sun, Chao, Carmillo, Paul, Sur, Gargi, Carulli, John P, Mansfield, Keith G, Westmoreland, Susan V, Staugaitis, Susan M, Fox, Robert J, Meier, Werner, Goelz, Susan E
• Format: Journal Article
• Language: English
• Published: United States Public Library of Science 18.05.2016; Public Library of Science (PLoS)
• Subjects: Acquired immune deficiency syndrome; Adults; Aged; AIDS; Analysis; Animals; Autopsies; Autopsy; Biology and Life Sciences; Biomedical research; Brain; Brain - metabolism; Brain - pathology; Brain - virology; Brain research; Capsid protein; CD11 antigen; Central nervous system; Coding; Correlation analysis; Demyelination; Deoxyribonucleic acid; Destruction; DNA; Encephalitis; Female; Gene expression; Health aspects; Histopathology; Humans; Immune system; Immunocompromised host; Immunologic factors; Immunology; Immunomodulation; Infections; JC virus; JC Virus - genetics; JC Virus - pathogenicity; JC Virus - physiology; Laboratories; Lesions; Leukoencephalopathy; Leukoencephalopathy, Progressive Multifocal - virology; Life cycle engineering; Life cycles; Localization; Macaca mulatta; Male; Medicine and Health Sciences; Monoclonal antibodies; Multiple sclerosis; Mutation; Myelin; Myelin Sheath - metabolism; Myelin Sheath - pathology; Myelin Sheath - virology; Nervous system; Neurology; Neurons; Neuropathology; Non-coding RNA; Pathogenesis; Pathology; Patients; Pharmacovigilance; Polyomavirus; Progressive multifocal leukoencephalopathy; Proteomics; Psoriasis; Regulatory sequences; Research and Analysis Methods; Risk factors; Skin diseases; Spatial analysis; Spatial distribution; Substantia alba; Viral Fusion Proteins - genetics; Viral infections; Viral Regulatory and Accessory Proteins - genetics; Virulence - genetics; Virus Replication; Viruses; VP1 protein; Cleveland Ohio; United States > US
• ISSN: 1932-6203; 1932-6203
• DOI: 10.1371/journal.pone.0155897

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 autopsy brain tissue from a 70-year-old psoriasis patient on the integrin alpha-L inhibitor efalizumab following a ~2 month clinical 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 agnoprotein, as well as 9 novel mutations in capsid protein VP2, indicating rampant viral evolution. Nine samples, including three gross PML lesions and normal-appearing adjacent tissues, were characterized by histopathology and subject to quantitative genomic, proteomic, and molecular localization 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.