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...
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| Format: | Article |
| Language: | English |
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eLife Sciences Publications Ltd
2022-11-01
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| Series: | eLife |
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| Online Access: | https://elifesciences.org/articles/83030 |
| _version_ | 1811309003274190848 |
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| author | Matthew D Lauver Ge Jin Katelyn N Ayers Sarah N Carey Charles S Specht Catherine S Abendroth Aron E Lukacher |
| author_facet | Matthew D Lauver Ge Jin Katelyn N Ayers Sarah N Carey Charles S Specht Catherine S Abendroth Aron E Lukacher |
| author_sort | Matthew D Lauver |
| collection | DOAJ |
| 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. |
| first_indexed | 2024-04-13T09:33:15Z |
| format | Article |
| id | doaj.art-7d6663b031074e5c9dc824121b5f54c6 |
| institution | Directory Open Access Journal |
| issn | 2050-084X |
| language | English |
| last_indexed | 2024-04-13T09:33:15Z |
| publishDate | 2022-11-01 |
| publisher | eLife Sciences Publications Ltd |
| record_format | Article |
| series | eLife |
| spelling | doaj.art-7d6663b031074e5c9dc824121b5f54c62022-12-22T02:52:10ZengeLife Sciences Publications LtdeLife2050-084X2022-11-011110.7554/eLife.83030T cell deficiency precipitates antibody evasion and emergence of neurovirulent polyomavirusMatthew D Lauver0https://orcid.org/0000-0002-7001-9730Ge Jin1Katelyn N Ayers2https://orcid.org/0000-0001-6156-8685Sarah N Carey3Charles S Specht4Catherine S Abendroth5Aron E Lukacher6https://orcid.org/0000-0002-7969-2841Department of Microbiology and Immunology, Pennsylvania State University, Hershey, United StatesDepartment of Microbiology and Immunology, Pennsylvania State University, Hershey, United StatesDepartment of Microbiology and Immunology, Pennsylvania State University, Hershey, United StatesDepartment of Microbiology and Immunology, Pennsylvania State University, Hershey, United StatesDepartment of Pathology and Laboratory Medicine, Penn State Milton S. Hershey Medical Center, Hershey, United StatesDepartment of Pathology and Laboratory Medicine, Penn State Milton S. Hershey Medical Center, Hershey, United StatesDepartment of Microbiology and Immunology, Pennsylvania State University, Hershey, United StatesJC 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.https://elifesciences.org/articles/83030polyomavirusantibody escapemouseneurovirulenceT cell deficiency |
| spellingShingle | Matthew D Lauver Ge Jin Katelyn N Ayers Sarah N Carey Charles S Specht Catherine S Abendroth Aron E Lukacher T cell deficiency precipitates antibody evasion and emergence of neurovirulent polyomavirus eLife polyomavirus antibody escape mouse neurovirulence T cell deficiency |
| 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 | polyomavirus antibody escape mouse neurovirulence T cell deficiency |
| url | https://elifesciences.org/articles/83030 |
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