Department of Microbiology and Immunology, Penn State College of Medicine, Hershey, United States
Ge Jin
Department of Microbiology and Immunology, Penn State College of Medicine, Hershey, United States
Daniel G Haas
Department of Microbiology and Immunology, Penn State College of Medicine, Hershey, United States
Elizabeth L Frost
Department of Microbiology and Immunology, Penn State College of Medicine, Hershey, United States
Sung Hyun Cho
Huck Institutes of the Life Sciences, Pennsylvania State University, University Park, United States
Carol M Bator
Huck Institutes of the Life Sciences, Pennsylvania State University, University Park, United States
Stephanie M Bywaters
Department of Pathology, Penn State College of Medicine, Hershey, United States; The Jake Gittlen Laboratories for Cancer Research, Penn State College of Medicine, Hershey, United States
Neil D Christensen
Department of Pathology, Penn State College of Medicine, Hershey, United States; The Jake Gittlen Laboratories for Cancer Research, Penn State College of Medicine, Hershey, United States
Susan L Hafenstein
Department of Biochemistry and Molecular Biology, Pennsylvania State University, University Park, United States; Huck Institutes of the Life Sciences, Pennsylvania State University, University Park, United States; Department of Medicine, Penn State College of Medicine, Hershey, United States
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.