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

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Abstract

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

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