CD4 T cell deficiency results in impaired neutralizing IgG against polyomavirus carrying a frequent PML-associated capsid mutation

Abstract

Abstract Deficiencies in the CD4 T cell compartment, such as HIV/AIDS, idiopathic CD4 lymphopenia, predispose patients to progressive multifocal leukoencephalopathy (PML), an oft-fatal demyelinating brain disease caused by the JC polyomavirus (JCPyV). PML is associated with immunomodulatory therapies that preferentially diminish CD4 T cells in the CSF (natalizumab) or B cells (rituximab). The connection between CD4 T cells and JCPyV control is unclear. Work by others show that PML patient sera have “blind spots” in neutralizing JCPyV variants with mutations in the VP1 capsid protein. We hypothesized that defects in the humoral response after CD4 T cell depletion led to the emergence of antibody (Ab)-escape PyV variants. Using mouse PyV (MuPyV) to model JCPyV CNS disease, we found immune cell aggregates consisting of B cells, CD4 T cells, and CD8 T cells along the ventricles of PyV-infected WT mice but only a few infected cells. In contrast, CD4 T cell-depleted mice had more infected ependyma but lacked lymphocytic aggregates. There were fewer anti-PyV Ab-secreting B cells in the CNS despite similar B cell numbers in MuPyV-infected WT and CD4 T cell deficient mice brains. CD4 T cells prevent emergence of VP1 mutant PyVs that escape neutralizing Abs. MuPyV infection elicits a CD4 T cell-independent anti-VP1 IgG response that neutralizes WT virus equivalently to IgG from CD4 T cell-sufficient mice. Serum from MHC-II KO and CD4 mAb depleted mice had significantly lower neutralization activity toward a MuPyV with a frequent PML-equivalent VP1 mutation than to WT MuPyV. This data demonstrate that a narrowed antiviral IgG response caused by CD4 T cell deficiency is a critical antecedent for outgrowth of Ab-escape PyV VP1 mutant viruses. Supported by 1. Finkelstein Memorial Student Research Award, Pennsylvania State University College of Medicine, Hershey, PA 2. T32 CA060395 Training Grant (Meyers), NIH/NCI 3. R01 NS088367, NIH/NCI