National Institutes of Health/National Institute of Neurological Disorders and Stroke (NIH/NINDS)
R01NS088367
United States
National Institutes of Health/National Institute Of Allergy and Infectious Diseases (NIH/NIAID)
R01AI107121
United States
National Institutes of Health/National Institute of Neurological Disorders and Stroke (NIH/NINDS)
R01NS092662
United States
National Institutes of Health/National Institute of Neurological Disorders and Stroke (NIH/NINDS)
F31NS083336
United States
National Institutes of Health/National Institute of Neurological Disorders and Stroke (NIH/NINDS)
F32NS106730
United States
National Institutes of Health/National Cancer Institute (NIH/NCI)
T32CA060395
United States
Citation
Journal: Elife / Year: 2020 Title: Antibody escape by polyomavirus capsid mutation facilitates neurovirulence. Authors: 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 / ...Authors: 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 / 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. ...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.
History
Deposition
Sep 9, 2020
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Header (metadata) release
Sep 23, 2020
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Map release
Sep 23, 2020
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Update
Oct 28, 2020
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Current status
Oct 28, 2020
Processing site: RCSB / Status: Released
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Structure visualization
Movie
Surface view with section colored by density value
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