title: JC virus reactivation during prolonged natalizumab monotherapy for multiple sclerosis.
abstract: OBJECTIVE
  To determine the prevalence of JC virus (JCV) reactivation and JCV-specific cellular immune response during prolonged natalizumab treatment for multiple sclerosis (MS).
  
  
  METHODS
  We enrolled 43 JCV-seropositive MS patients, including 32 on natalizumab monotherapy >18 months, 6 on interferon β-1a monotherapy >36 months, and 5 untreated controls. We performed quantitative real-time polymerase chain reaction in cerebrospinal fluid (CSF), blood, and urine for JCV DNA, and we determined JCV-specific T-cell responses using enzyme-linked immunosorbent spot (ELISpot) and intracellular cytokine staining (ICS) assays, ex vivo and after in vitro stimulation with JCV peptides.
  
  
  RESULTS
  JCV DNA was detected in the CSF of 2 of 27 (7.4%) natalizumab-treated MS patients who had no symptoms or magnetic resonance imaging-detected lesions consistent with progressive multifocal leukoencephalopathy. JCV DNA was detected in blood of 12 of 43 (27.9%) and in urine of 11 of 43 (25.6%) subjects without a difference between natalizumab-treated patients and controls. JC viral load was higher in CD34(+) cells and in monocytes compared to other subpopulations. ICS was more sensitive than ELISpot. JCV-specific T-cell responses, mediated by both CD4(+) and CD8(+) T lymphocytes, were detected more frequently after in vitro stimulation. JCV-specific CD4(+) T cells were detected ex vivo more frequently in MS patients with JCV DNA in CD34(+) (p = 0.05) and B cells (p = 0.03).
  
  
  CONCLUSIONS
  Asymptomatic JCV reactivation may occur in CSF of natalizumab-treated MS patients. JCV DNA load is higher in circulating CD34(+) cells and monocytes compared to other mononuclear cells, and JCV in blood might trigger a JCV-specific CD4(+) T-cell response. JCV-specific cellular immune response is highly prevalent in all JCV-seropositive MS patients, regardless of treatment.
authors.affiliation: Division of NeuroVirology, Center for Virology and Vaccine Research, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston; Division of Infectious Diseases, Department of Medicine, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston.
authors.forename: Spyridon
authors.initials: S
authors.lastname: Chalkias
authors.forename: Xin
authors.initials: X
authors.lastname: Dang
authors.forename: Evelyn
authors.initials: E
authors.lastname: Bord
authors.forename: Marion C
authors.initials: MC
authors.lastname: Stein
authors.forename: R Philip
authors.initials: RP
authors.lastname: Kinkel
authors.forename: Jacob A
authors.initials: JA
authors.lastname: Sloane
authors.forename: Maureen
authors.initials: M
authors.lastname: Donnelly
authors.forename: Carolina
authors.initials: C
authors.lastname: Ionete
authors.forename: Maria K
authors.initials: MK
authors.lastname: Houtchens
authors.forename: Guy J
authors.initials: GJ
authors.lastname: Buckle
authors.forename: Stephanie
authors.initials: S
authors.lastname: Batson
authors.forename: Igor J
authors.initials: IJ
authors.lastname: Koralnik
mesh_terms: D000328:Adult; D000368:Aged; D061067:Antibodies, Monoclonal, Humanized / Q000627:therapeutic use*; D004279:DNA, Viral / Q000097:blood / Q000134:cerebrospinal fluid / Q000652:urine; D004797:Enzyme-Linked Immunosorbent Assay; D005260:Female; D005500:Follow-Up Studies; D006801:Humans; D007155:Immunologic Factors / Q000627:therapeutic use*; D000068556:Interferon beta-1a; D016899:Interferon-beta / Q000627:therapeutic use; D007371:Interferon-gamma / Q000378:metabolism; D007577:JC Virus / Q000235:genetics; D008297:Male; D008875:Middle Aged; D009103:Multiple Sclerosis / Q000150:complications / Q000188:drug therapy* / Q000453:epidemiology / Q000821:virology; D000069442:Natalizumab; D027601:Polyomavirus Infections / Q000150:complications / Q000453:epidemiology; D012189:Retrospective Studies; D013223:Statistics as Topic; D013601:T-Lymphocytes / Q000378:metabolism; D013997:Time Factors
chemical_list: D061067:Antibodies, Monoclonal, Humanized; D004279:DNA, Viral; D007155:Immunologic Factors; D000069442:Natalizumab; D016899:Interferon-beta; D007371:Interferon-gamma; D000068556:Interferon beta-1a