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


Jelcic, Ivan; Jelcic, Ilijas; Kempf, Christian; Largey, Fabienne; Planas, Raquel; Schippling, Sven; Budka, Herbert; Sospedra, Mireia; Martin, Roland (2016). Mechanisms of immune escape in central nervous system infection with neurotropic JC virus variant. Annals of Neurology, 79(3):404-418.

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 CD4(dim) CD8(+) 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.

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 CD4(dim) CD8(+) 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.

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2 citations in Scopus®
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Additional indexing

Item Type:Journal Article, refereed, original work
Communities & Collections:04 Faculty of Medicine > University Hospital Zurich > Clinic for Neurology
Dewey Decimal Classification:610 Medicine & health
Language:English
Date:13 February 2016
Deposited On:01 Mar 2016 18:22
Last Modified:05 Apr 2016 20:10
Publisher:Wiley-Blackwell Publishing, Inc.
ISSN:0364-5134
Publisher DOI:https://doi.org/10.1002/ana.24574
PubMed ID:26874214

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