title: Mechanisms of immune escape in central nervous system infection with neurotropic JC virus variant.
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.
  
  
  CONCLUSIONS
  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.
authors.affiliation: Neuroimmunology and Multiple Sclerosis Research Section, Department of Neurology University Hospital Zurich, Zurich, Switzerland.
authors.forename: Ivan
authors.initials: I
authors.lastname: Jelcic
authors.affiliation: Neuroimmunology and Multiple Sclerosis Research Section, Department of Neurology University Hospital Zurich, Zurich, Switzerland.
authors.forename: Ilijas
authors.initials: I
authors.lastname: Jelcic
authors.affiliation: Neuroimmunology and Multiple Sclerosis Research Section, Department of Neurology University Hospital Zurich, Zurich, Switzerland.
authors.forename: Christian
authors.initials: C
authors.lastname: Kempf
authors.affiliation: Neuroimmunology and Multiple Sclerosis Research Section, Department of Neurology University Hospital Zurich, Zurich, Switzerland.
authors.forename: Fabienne
authors.initials: F
authors.lastname: Largey
authors.affiliation: Neuroimmunology and Multiple Sclerosis Research Section, Department of Neurology University Hospital Zurich, Zurich, Switzerland.
authors.forename: Raquel
authors.initials: R
authors.lastname: Planas
authors.affiliation: Neuroimmunology and Multiple Sclerosis Research Section, Department of Neurology University Hospital Zurich, Zurich, Switzerland.
authors.forename: Sven
authors.initials: S
authors.lastname: Schippling
authors.affiliation: Institute of Neuropathology, University Hospital Zurich, Zurich, Switzerland.
authors.forename: Herbert
authors.initials: H
authors.lastname: Budka
authors.affiliation: Neuroimmunology and Multiple Sclerosis Research Section, Department of Neurology University Hospital Zurich, Zurich, Switzerland.
authors.forename: Mireia
authors.initials: M
authors.lastname: Sospedra
authors.affiliation: Neuroimmunology and Multiple Sclerosis Research Section, Department of Neurology University Hospital Zurich, Zurich, Switzerland.
authors.forename: Roland
authors.initials: R
authors.lastname: Martin
mesh_terms: D000328:Adult; D001921:Brain / Q000276:immunology / Q000821:virology; D005260:Female; D006801:Humans; D057131:Immune Evasion / Q000276:immunology*; D054019:Immune Reconstitution Inflammatory Syndrome / Q000276:immunology* / Q000821:virology; D007577:JC Virus / Q000145:classification / Q000235:genetics / Q000502:physiology*; D007968:Leukoencephalopathy, Progressive Multifocal / Q000276:immunology* / Q000821:virology*; D008297:Male; D008875:Middle Aged; D009103:Multiple Sclerosis / Q000276:immunology* / Q000821:virology