Mechanisms of immune escape in central nervous system infection with neurotropic JC virus variant

Objective Symptomatic infections of the central nervous system (CNS) with JC polyomavirus (JCV) usually occur as a result of immunocompromise and manifest as progressive multifocal leukoencephalopathy (PML) or granule cell neuronopathy (GCN). After immune reconstitution, some of these cases may show long‐term persistence of JCV and delayed clinical improvement despite inflammation. Methods We followed 4 patients with multiple sclerosis, who developed natalizumab‐associated PML or GCN with regard to JC viral load and JCV‐specific T‐cell responses in the CNS. All of them experienced immune reconstitution inflammatory syndrome (IRIS), but in 2 cases JCV persisted > 21 months after IRIS accompanied by delayed clinical improvement. Results Persistence of JCV was associated with a lack of JCV VP1‐specific T‐cell responses during immune reconstitution in 1 of the patients. Detailed analysis of the brain infiltrate in another patient with neuronal persistence of JCV revealed strong infiltration of CD8+ T cells and clonal expansion of activated CD8+ effector T cells with a CD4dimCD8+ phenotype, both exhibiting exquisite specificity for conserved epitopes of JCV large T antigen. However, clearance of JCV was not efficient, because mutations in the major capsid protein VP1 caused reduced CD4+ T‐cell responses against the identified JCV variant and subsequently resulted in a decline of CD8+ T‐cell responses after IRIS. Interpretation Our findings suggest that efficient CD4+ T‐cell recognition of neurotropic JCV variants is crucial to support CD8+ T cells in combating JCV infection of the CNS. ANN NEUROL 2016;79:404–418