title: JC Polyomavirus Abundance and Distribution in Progressive Multifocal Leukoencephalopathy (PML) Brain Tissue Implicates Myelin Sheath in Intracerebral Dissemination of Infection.
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 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.
authors.affiliation: Translational Pathology Laboratory, Biogen Inc., Cambridge, MA, United States of America.
authors.forename: Keith A
authors.initials: KA
authors.lastname: Wharton
authors.affiliation: Translational Pathology Laboratory, Biogen Inc., Cambridge, MA, United States of America.
authors.forename: Catherine
authors.initials: C
authors.lastname: Quigley
authors.affiliation: Translational Pathology Laboratory, Biogen Inc., Cambridge, MA, United States of America.
authors.forename: Marian
authors.initials: M
authors.lastname: Themeles
authors.affiliation: Translational Pathology Laboratory, Biogen Inc., Cambridge, MA, United States of America.
authors.forename: Robert W
authors.initials: RW
authors.lastname: Dunstan
authors.affiliation: Immunology, Biogen Inc., Cambridge, MA, United States of America.
authors.forename: Kathryn
authors.initials: K
authors.lastname: Doyle
authors.affiliation: Immunology, Biogen Inc., Cambridge, MA, United States of America.
authors.forename: Ellen
authors.initials: E
authors.lastname: Cahir-McFarland
authors.affiliation: Bioanalytical Chemistry, Biogen Inc., Cambridge, MA, United States of America.
authors.forename: Jing
authors.initials: J
authors.lastname: Wei
authors.affiliation: Bioanalytical Chemistry, Biogen Inc., Cambridge, MA, United States of America.
authors.forename: Alex
authors.initials: A
authors.lastname: Buko
authors.affiliation: Molecular Discovery, Biogen Inc., Cambridge, MA, United States of America.
authors.forename: Carl E
authors.initials: CE
authors.lastname: Reid
authors.affiliation: Molecular Discovery, Biogen Inc., Cambridge, MA, United States of America.
authors.forename: Chao
authors.initials: C
authors.lastname: Sun
authors.affiliation: Molecular Discovery, Biogen Inc., Cambridge, MA, United States of America.
authors.forename: Paul
authors.initials: P
authors.lastname: Carmillo
authors.affiliation: Molecular Discovery, Biogen Inc., Cambridge, MA, United States of America.
authors.forename: Gargi
authors.initials: G
authors.lastname: Sur
authors.affiliation: Molecular Discovery, Biogen Inc., Cambridge, MA, United States of America.
authors.forename: John P
authors.initials: JP
authors.lastname: Carulli
authors.affiliation: Department of Pathology, Harvard Medical School, New England Primate Research Center, Southborough, MA, United States of America.
authors.forename: Keith G
authors.initials: KG
authors.lastname: Mansfield
authors.affiliation: Department of Pathology, Harvard Medical School, New England Primate Research Center, Southborough, MA, United States of America.
authors.forename: Susan V
authors.initials: SV
authors.lastname: Westmoreland
authors.affiliation: Departments of Pathology, Neurosciences, and Mellen Center for Multiple Sclerosis, Cleveland Clinic, Cleveland, OH, United States of America.
authors.forename: Susan M
authors.initials: SM
authors.lastname: Staugaitis
authors.affiliation: Mellen Center for Multiple Sclerosis, Cleveland Clinic, Cleveland, OH, United States of America.
authors.forename: Robert J
authors.initials: RJ
authors.lastname: Fox
authors.affiliation: Discovery Sciences, Biogen Inc, Cambridge, MA, United States of America.
authors.forename: Werner
authors.initials: W
authors.lastname: Meier
authors.affiliation: Neurology, Biogen Inc, Cambridge, MA, United States of America.
authors.forename: Susan E
authors.initials: SE
authors.lastname: Goelz
mesh_terms: D000368:Aged; D000818:Animals; D001921:Brain / Q000378:metabolism / Q000473:pathology / Q000821:virology*; D005260:Female; D006801:Humans; D007577:JC Virus / Q000235:genetics / Q000472:pathogenicity* / Q000502:physiology; D007968:Leukoencephalopathy, Progressive Multifocal / Q000821:virology*; D008253:Macaca mulatta; D008297:Male; D009154:Mutation; D009186:Myelin Sheath / Q000378:metabolism* / Q000473:pathology / Q000821:virology; D014760:Viral Fusion Proteins / Q000235:genetics; D054334:Viral Regulatory and Accessory Proteins / Q000235:genetics; D014774:Virulence / Q000235:genetics; D014779:Virus Replication; D000086082:Viroporin Proteins
chemical_list: D014760:Viral Fusion Proteins; D054334:Viral Regulatory and Accessory Proteins; C042559:agnoprotein, polyomavirus; D000086082:Viroporin Proteins