T cell deficiency precipitates antibody evasion and emergence of neurovirulent polyomavirus
- Pennsylvania State University, United States
- Penn State Milton S. Hershey Medical Center, United States
Abstract
JC polyomavirus (JCPyV) causes progressive multifocal leukoencephalopathy (PML), a life-threatening brain disease in immunocompromised patients. Inherited and acquired T cell deficiencies are associated with PML. The incidence of PML is increasing with the introduction of new immunomodulatory agents, several of which target T cells or B cells. PML patients often carry mutations in the JCPyV VP1 capsid protein, which confer resistance to neutralizing VP1 antibodies (Ab). Polyomaviruses (PyV) are tightly species-specific; the absence of tractable animal models has handicapped understanding PyV pathogenesis. Using mouse polyomavirus (MuPyV), we found that T cell deficiency during persistent infection, in the setting of monospecific VP1 Ab, was required for outgrowth of VP1 Ab-escape viral variants. CD4 T cells were primarily responsible for limiting polyomavirus infection in the kidney, a major reservoir of persistent infection by both JCPyV and MuPyV, and checking emergence of these mutant viruses. T cells also provided a second line of defense by controlling the outgrowth of VP1 mutant viruses that evaded Ab neutralization. A virus with two capsid mutations, one conferring Ab-escape yet impaired infectivity and a second compensatory mutation, yielded a highly neurovirulent variant. These findings link T cell deficiency and evolution of Ab-escape polyomavirus VP1 variants with neuropathogenicity.
Data availability
All data files are uploaded as Source data files with this manuscript. Images are deposited with Dryad at (https://doi.org/10.5061/dryad.prr4xgxqj).
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T cell deficiency precipitates antibody evasion and emergence of neurovirulent polyomavirusDryad Digital Repository, doi:10.5061/dryad.prr4xgxqj.
Article and author information
Author details
Funding
National Institutes of Health (5R01NS088367)
- Aron E Lukacher
National Institutes of Health (5R01NS092662)
- Aron E Lukacher
National Institutes of Health (R35NS127217)
- Aron E Lukacher
The funders had no role in study design, data collection and interpretation, or the decision to submit the work for publication.
Ethics
Animal experimentation: This study was performed in strict accordance with the recommendations in the Guide for the Care and Use of Laboratory Animals of the National Institutes of Health. All of the animals were handled according to an approved institutional animal care and use committee (IACUC) protocol (#PRAMS201447619) of The Pennsylvania State University.
Reviewing Editor
- Karla Kirkegaard, Stanford University School of Medicine, United States
Version history
- Preprint posted: February 25, 2022 (view preprint)
- Received: August 26, 2022
- Accepted: October 4, 2022
- Accepted Manuscript published: November 7, 2022 (version 1)
- Version of Record published: November 18, 2022 (version 2)
Copyright
© 2022, 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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T cell deficiency precipitates antibody evasion and emergence of neurovirulent polyomavirus
eLife 11:e83030.
https://doi.org/10.7554/eLife.83030
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