T cell insufficiency enables emergence of polyomavirus antibody escape variants

Abstract

Abstract Deficient adaptive immunity underlies CNS diseases caused by JC polyomavirus (JCPyV), a ubiquitous member of the human virome. The best characterized of these is progressive multifocal leukoencephalopathy (PML), a frequently fatal brain demyelinating disease. Risk factors for PML are poorly defined but mainly involve conditions of T cell insufficiency or dysfunction, including AIDS and particular immunomodulatory therapies (natalizumab, rituximab). JCPyV isolates from PML patients’ brains frequently contain point mutations in the major capsid protein, VP1. However, these variants are not present in the patients’ kidneys, the major site of JCPyV persistence. How/if these mutations confer neurovirulence is actively debated. Mapping a common JCPyV-PML VP1 mutation into mouse polyomavirus (MuPyV), we found that this variant virus was resistant to a neutralizing monoclonal antibody (mAb) and poorly replicated in the kidney. Cryo EM analysis unambiguously defined the antibody epitope and identified the mechanism of antibody escape. Passaging MuPyV in the presence of VP1 mAb allowed emergence of antibody escape variants in vitro. To investigate the connection between T cell impairment and antibody escape in vivo, we infected antibody-deficient μMT mice with MuPyV, treated them with VP1 mAb, then subjected them to CD4 and CD8 antibody-mediated T cell depletion during persistent infection. In contrast to non-T cell depleted mice, which maintained long term control over MuPyV infection, T cell depletion led to lethal MuPyV disease resulting from the outgrowth of antibody-escape variants. These data show that a narrow PyV antibody response compounded by T cell insufficiency promotes emergence of nAb escape neurotropic variants.