T Cell Deficiency Precipitates Antibody Evasion and Emergence of Neurovirulent Polyomavirus

Abstract

JC polyomavirus (JCPyV) causes Progressive Multifocal Leukoencephalopathy (PML), a life-threatening brain disease in T cell immunosuppressed patients. PML patients often carry mutations in the JCPyV VP1 capsid protein. These mutations confer resistance to neutralizing VP1 antibodies (Ab). We found that T cell insufficiency 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 preventing resurgent virus infection in the kidney and checking emergence of these mutant viruses. T cells also provided a second line of defense against Ab-escape VP1 mutant viruses. 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.