{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,6]],"date-time":"2026-10-06T17:45:04Z","timestamp":1791308704131,"version":"4.3.1"},"reference-count":39,"publisher":"Wiley","issue":"3","license":[{"start":{"date-parts":[[2016,2,13]],"date-time":"2016-02-13T00:00:00Z","timestamp":1455321600000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/onlinelibrary.wiley.com\/termsAndConditions#vor"}],"funder":[{"name":"Clinical Research Priority Program on Multiple Sclerosis"},{"DOI":"10.13039\/501100008486","name":"Swiss Multiple Sclerosis Society","doi-asserted-by":"crossref","id":[{"id":"10.13039\/501100008486","id-type":"DOI","asserted-by":"crossref"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Annals of Neurology"],"published-print":{"date-parts":[[2016,3]]},"abstract":"<jats:sec><jats:title>Objective<\/jats:title><jats:p>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\u2010term persistence of JCV and delayed clinical improvement despite inflammation.<\/jats:p><\/jats:sec><jats:sec><jats:title>Methods<\/jats:title><jats:p>We followed 4 patients with multiple sclerosis, who developed natalizumab\u2010associated PML or GCN with regard to JC viral load and JCV\u2010specific T\u2010cell responses in the CNS. All of them experienced immune reconstitution inflammatory syndrome (IRIS), but in 2 cases JCV persisted\u2009&gt;\u200921 months after IRIS accompanied by delayed clinical improvement.<\/jats:p><\/jats:sec><jats:sec><jats:title>Results<\/jats:title><jats:p>Persistence of JCV was associated with a lack of JCV VP1\u2010specific T\u2010cell 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<jats:sup>+<\/jats:sup> T cells and clonal expansion of activated CD8<jats:sup>+<\/jats:sup> effector T cells with a CD4<jats:sup>dim<\/jats:sup>CD8<jats:sup>+<\/jats:sup> 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<jats:sup>+<\/jats:sup> T\u2010cell responses against the identified JCV variant and subsequently resulted in a decline of CD8<jats:sup>+<\/jats:sup> T\u2010cell responses after IRIS.<\/jats:p><\/jats:sec><jats:sec><jats:title>Interpretation<\/jats:title><jats:p>Our findings suggest that efficient CD4<jats:sup>+<\/jats:sup> T\u2010cell recognition of neurotropic JCV variants is crucial to support CD8<jats:sup>+<\/jats:sup> T cells in combating JCV infection of the CNS. 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