title: JC polyomavirus mutants escape antibody-mediated neutralization.
abstract: JC polyomavirus (JCV) persistently infects the urinary tract of most adults. Under conditions of immune impairment, JCV causes an opportunistic brain disease, progressive multifocal leukoencephalopathy (PML). JCV strains found in the cerebrospinal fluid of PML patients contain distinctive mutations in surface loops of the major capsid protein, VP1. We hypothesized that VP1 mutations might allow the virus to evade antibody-mediated neutralization. Consistent with this hypothesis, neutralization serology revealed that plasma samples from PML patients neutralized wild-type JCV strains but failed to neutralize patient-cognate PML-mutant JCV strains. This contrasted with serological results for healthy individuals, most of whom robustly cross-neutralized all tested JCV variants. Mice administered a JCV virus-like particle (VLP) vaccine initially showed neutralizing "blind spots" (akin to those observed in PML patients) that closed after booster immunization. A PML patient administered an experimental JCV VLP vaccine likewise showed markedly increased neutralizing titer against her cognate PML-mutant JCV. The results indicate that deficient humoral immunity is a common aspect of PML pathogenesis and that vaccination may overcome this humoral deficiency. Thus, vaccination with JCV VLPs might prevent the development of PML.
authors.affiliation: Lab of Cellular Oncology, Center for Cancer Research, National Cancer Institute, Bethesda, MD 20892, USA.
authors.forename: Upasana
authors.initials: U
authors.lastname: Ray
authors.affiliation: Department of Infectious Diseases, San Raffaele Scientific Institute, 20132 Milan, Italy.
authors.forename: Paola
authors.initials: P
authors.lastname: Cinque
authors.affiliation: Neuroradiology Unit, Head and Neck Department, San Raffaele Scientific Institute, 20132 Milan, Italy.
authors.forename: Simonetta
authors.initials: S
authors.lastname: Gerevini
authors.affiliation: Department of Infectious Diseases, San Raffaele Scientific Institute, 20132 Milan, Italy.
authors.forename: Valeria
authors.initials: V
authors.lastname: Longo
authors.affiliation: Department of Infectious Diseases, San Raffaele Scientific Institute, 20132 Milan, Italy. San Raffaele University, 20132 Milan, Italy.
authors.forename: Adriano
authors.initials: A
authors.lastname: Lazzarin
authors.affiliation: Neuroimmunology and Multiple Sclerosis Research Section, Department of Neurology, University Hospital Zurich, University Zurich, 8091 Zurich, Switzerland.
authors.forename: Sven
authors.initials: S
authors.lastname: Schippling
authors.affiliation: Neuroimmunology and Multiple Sclerosis Research Section, Department of Neurology, University Hospital Zurich, University Zurich, 8091 Zurich, Switzerland.
authors.forename: Roland
authors.initials: R
authors.lastname: Martin
authors.affiliation: Lab of Cellular Oncology, Center for Cancer Research, National Cancer Institute, Bethesda, MD 20892, USA. buckc@mail.nih.gov pastrand@mail.nih.gov.
authors.forename: Christopher B
authors.initials: CB
authors.lastname: Buck
authors.affiliation: Lab of Cellular Oncology, Center for Cancer Research, National Cancer Institute, Bethesda, MD 20892, USA. buckc@mail.nih.gov pastrand@mail.nih.gov.
authors.forename: Diana V
authors.initials: DV
authors.lastname: Pastrana
mesh_terms: D006801:Humans; D057131:Immune Evasion; D007577:JC Virus / Q000235:genetics / Q000276:immunology / Q000472:pathogenicity*; D009154:Mutation; D009500:Neutralization Tests; D014765:Viral Vaccines / Q000008:administration & dosage
chemical_list: D014765:Viral Vaccines