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T cell deficiency precipitates antibody evasion and emergence of neurovirulent polyomavirus

Citation

Lukacher, Aron et al. (2022), T cell deficiency precipitates antibody evasion and emergence of neurovirulent polyomavirus, Dryad, Dataset, https://doi.org/10.5061/dryad.prr4xgxqj

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 of 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.

Methods

The data files were generated on a Leica DM4000 fluorescence microscope.

Usage Notes

Leica Application Suite X (LAS X) or Fiji/ImageJ with the Bio-Formats plugin is required to open the .lif files.

Funding

National Institutes of Health, Award: R35NS127217

National Institutes of Health, Award: R01NS092662

National Institutes of Health, Award: R01NS088367