RT Journal Article
SR Electronic
T1 Antibody Escape by Polyomavirus Capsid Mutation Facilitates Neurovirulence
JF bioRxiv
FD Cold Spring Harbor Laboratory
SP 2020.07.14.203281
DO 10.1101/2020.07.14.203281
A1 Matthew D. Lauver
A1 Daniel J. Goetschius
A1 Colleen S. Netherby-Winslow
A1 Katelyn N. Ayers
A1 Ge Jin
A1 Daniel G. Haas
A1 Elizabeth L. Frost
A1 Sung Hyun Cho
A1 Carol M. Bator
A1 Stephanie M. Bywaters
A1 Neil D. Christensen
A1 Susan L. Hafenstein
A1 Aron E. Lukacher
YR 2020
UL http://biorxiv.org/content/early/2020/07/15/2020.07.14.203281.abstract
AB 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 subvolume refinement approach, we resolved an MuPyV:Fab complex map to 3.1 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.Competing Interest StatementThe authors have declared no competing interest.