Antibody escape by polyomavirus capsid mutation facilitates neurovirulence

Elife. 2020 Sep 17;9:e61056. doi: 10.7554/eLife.61056.

Abstract

JCPyV polyomavirus, a member of the human virome, causes progressive multifocal leukoencephalopathy (PML), an oft-fatal demyelinating brain disease in individuals receiving immunomodulatory therapies. Mutations in the major viral capsid protein, VP1, are common in JCPyV from PML patients (JCPyV-PML) but whether they confer neurovirulence or escape from virus-neutralizing antibody (nAb) in vivo is unknown. A mouse polyomavirus (MuPyV) with a sequence-equivalent JCPyV-PML VP1 mutation replicated poorly in the kidney, a major reservoir for JCPyV persistence, but retained the CNS infectivity, cell tropism, and neuropathology of the parental virus. This mutation rendered MuPyV resistant to a monoclonal Ab (mAb), whose specificity overlapped the endogenous anti-VP1 response. Using cryo-EM and a custom sub-particle refinement approach, we resolved an MuPyV:Fab complex map to 3.2 Å resolution. The structure revealed the mechanism of mAb evasion. Our findings demonstrate convergence between nAb evasion and CNS neurovirulence in vivo by a frequent JCPyV-PML VP1 mutation.

Keywords: Cryo EM; fab:capsid complex; immunology; inflammation; mouse; neutralizing antibody; polyomavirus; progressive multifocal leukoencephalopathy; subvolume refinement.

Publication types

  • Research Support, N.I.H., Extramural

MeSH terms

  • Animals
  • Antibodies, Monoclonal / immunology*
  • Capsid / immunology*
  • Female
  • Leukoencephalopathy, Progressive Multifocal / immunology
  • Male
  • Mice
  • Mice, Inbred C57BL
  • Mutation*
  • Polyomavirus / immunology
  • Polyomavirus / pathogenicity*
  • Virulence

Substances

  • Antibodies, Monoclonal