Antibody escape by polyomavirus capsid mutation facilitates neurovirulence

Matthew D. Lauver, Daniel J. Goetschius, Colleen S. Netherby-Winslow, Katelyn N. Ayers, Ge Jin, Daniel G. Haas, Elizabeth L. Frost, Sung Hyun Cho, Carol M. Bator, Stephanie M. Bywaters, Neil D. Christensen, Susan L. Hafenstein, Aron E. Lukacher

Research output: Contribution to journalArticlepeer-review

6 Scopus citations


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.

Original languageEnglish (US)
Pages (from-to)1-68
Number of pages68
StatePublished - Sep 2020

All Science Journal Classification (ASJC) codes

  • Neuroscience(all)
  • Biochemistry, Genetics and Molecular Biology(all)
  • Immunology and Microbiology(all)


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