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T cell deficiency precipitates antibody evasion and emergence of neurovirulent polyomavirus
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...
Autores principales: | , , , , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
eLife Sciences Publications, Ltd
2022
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Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9674346/ https://www.ncbi.nlm.nih.gov/pubmed/36341713 http://dx.doi.org/10.7554/eLife.83030 |
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author | Lauver, Matthew D Jin, Ge Ayers, Katelyn N Carey, Sarah N Specht, Charles S Abendroth, Catherine S Lukacher, Aron E |
author_facet | Lauver, Matthew D Jin, Ge Ayers, Katelyn N Carey, Sarah N Specht, Charles S Abendroth, Catherine S Lukacher, Aron E |
author_sort | Lauver, Matthew D |
collection | PubMed |
description | 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. |
format | Online Article Text |
id | pubmed-9674346 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2022 |
publisher | eLife Sciences Publications, Ltd |
record_format | MEDLINE/PubMed |
spelling | pubmed-96743462022-11-19 T cell deficiency precipitates antibody evasion and emergence of neurovirulent polyomavirus Lauver, Matthew D Jin, Ge Ayers, Katelyn N Carey, Sarah N Specht, Charles S Abendroth, Catherine S Lukacher, Aron E eLife Microbiology and Infectious Disease 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. eLife Sciences Publications, Ltd 2022-11-07 /pmc/articles/PMC9674346/ /pubmed/36341713 http://dx.doi.org/10.7554/eLife.83030 Text en © 2022, Lauver et al https://creativecommons.org/licenses/by/4.0/This article is distributed under the terms of the Creative Commons Attribution License (https://creativecommons.org/licenses/by/4.0/) , which permits unrestricted use and redistribution provided that the original author and source are credited. |
spellingShingle | Microbiology and Infectious Disease Lauver, Matthew D Jin, Ge Ayers, Katelyn N Carey, Sarah N Specht, Charles S Abendroth, Catherine S Lukacher, Aron E T cell deficiency precipitates antibody evasion and emergence of neurovirulent polyomavirus |
title | T cell deficiency precipitates antibody evasion and emergence of neurovirulent polyomavirus |
title_full | T cell deficiency precipitates antibody evasion and emergence of neurovirulent polyomavirus |
title_fullStr | T cell deficiency precipitates antibody evasion and emergence of neurovirulent polyomavirus |
title_full_unstemmed | T cell deficiency precipitates antibody evasion and emergence of neurovirulent polyomavirus |
title_short | T cell deficiency precipitates antibody evasion and emergence of neurovirulent polyomavirus |
title_sort | t cell deficiency precipitates antibody evasion and emergence of neurovirulent polyomavirus |
topic | Microbiology and Infectious Disease |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9674346/ https://www.ncbi.nlm.nih.gov/pubmed/36341713 http://dx.doi.org/10.7554/eLife.83030 |
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