Antibody escape by polyomavirus capsid mutation facilitates neurovirulence
- Penn State College of Medicine, United States
- The Pennsylvania State University, United States
- University of Virginia, United States
- Huck Institutes of the Life Sciences, United States
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.
Data availability
All maps and models are deposited at wwPDB and their accession numbers are provided in the Data and code availability section of our manuscript.Maps and coordinates (4 zip files) generated during this study are included in the manuscript and supporting files.Source data files have been provided for Figures 4 and 5 and for Supplemental Figure 4, and are available on GitHub with the URL provided in the Data and code availability section.
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Murine polyomavirus pentavalent capsomer, subparticle reconstructionProtein Data Bank, 7K24.
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Murine polyomavirus hexavalent capsomer, subparticle reconstructionProtein Data Bank, 7K25.
Article and author information
Author details
Daniel J Goetschius
Funding
National Institute of Neurological Disorders and Stroke (R01NS088367)
- Aron E Lukacher
National Institute of Neurological Disorders and Stroke (R01NS092662)
- Aron E Lukacher
National Institute of Allergy and Infectious Diseases (R01AI107121)
- Susan L Hafenstein
National Institute of Neurological Disorders and Stroke (F32NS106730)
- Colleen S Netherby-Winslow
National Institute of Neurological Disorders and Stroke (F31NS083336)
- Elizabeth L Frost
National Cancer Institute (T32CA060395)
- Matthew D Lauver
National Cancer Institute (T32CA60395)
- Stephanie M Bywaters
The funders had no role in study design, data collection and interpretation, or the decision to submit the work for publication.
Reviewing Editor
- John W Schoggins, University of Texas Southwestern Medical Center, United States
Ethics
Animal experimentation: All experiments involving mice were conducted with the approval of Institutional Animal Care and Use Committee (Protocol 47619) of The Pennsylvania State University College of Medicine in accordance with the Guide for the Care and Use of Laboratory Animals of the National Institutes of Health. The Pennsylvania State University College of Medicine Animal Resource Program is accredited by the Association for Assessment and Accreditation of Laboratory Animal Care International (AAALAC). The Pennsylvania State University College of Medicine has an Animal Welfare Assurance on file with the National Institutes of Health's Office of Laboratory Animal Welfare; the Assurance Number is A3045-01.
Version history
- Received: July 14, 2020
- Accepted: September 17, 2020
- Accepted Manuscript published: September 17, 2020 (version 1)
- Version of Record published: October 7, 2020 (version 2)
- Version of Record updated: October 9, 2020 (version 3)
Copyright
© 2020, Lauver et al.
This article is distributed under the terms of the Creative Commons Attribution License permitting unrestricted use and redistribution provided that the original author and source are credited.
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Antibody escape by polyomavirus capsid mutation facilitates neurovirulence
eLife 9:e61056.
https://doi.org/10.7554/eLife.61056
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