title: Asymptomatic reactivation of JC virus in patients treated with natalizumab.
abstract: BACKGROUND
  Progressive multifocal leukoencephalopathy (PML) occurs in a fraction of patients with multiple sclerosis who were treated with natalizumab. Most adults who are infected with the JC virus, the etiologic agent in PML, do not have symptoms. We sought to determine whether exposure to natalizumab causes subclinical reactivation and neurotropic transformation of JC virus.
  
  
  METHODS
  We followed 19 consecutive patients with multiple sclerosis who were treated with natalizumab over an 18-month period, performing quantitative polymerase-chain-reaction assays in blood and urine for JC virus reactivation; BK virus, a JC virus-related polyomavirus, was used as a control. We determined JC virus-specific T-cell responses by means of an enzyme-linked immunospot assay and antibody responses by means of an enzyme-linked immunosorbent assay and analyzed JC virus regulatory-region sequences.
  
  
  RESULTS
  After 12 months of natalizumab therapy, the prevalence of JC virus in the urine of the 19 patients increased from a baseline value of 19% to 63% (P=0.02). After 18 months of treatment, JC virus was detectable in 3 of 15 available plasma samples (20%) and in 9 of 15 available samples of peripheral-blood mononuclear cells (60%) (P=0.02). JC virus regulatory-region sequences in blood samples and in most of the urine samples were similar to those usually found in PML. Conversely, BK virus remained stable in urine and was undetectable in blood. The JC virus-specific cellular immune response dropped significantly between 6 and 12 months of treatment, and variations in the cellular immune response over time tended to be greater in patients in whom JC viremia developed. None of the patients had clinical or radiologic signs of PML.
  
  
  CONCLUSIONS
  Subclinical reactivation of JC virus occurs frequently in natalizumab-treated patients with multiple sclerosis. Viral shedding is associated with a transient drop in the JC virus-specific cellular immune response.
authors.affiliation: Division of Viral Pathogenesis, Beth Israel Deaconess Medical Center, and Harvard Medical School, Boston, MA 02215, USA.
authors.forename: Yiping
authors.initials: Y
authors.lastname: Chen
authors.forename: Evelyn
authors.initials: E
authors.lastname: Bord
authors.forename: Troy
authors.initials: T
authors.lastname: Tompkins
authors.forename: Janice
authors.initials: J
authors.lastname: Miller
authors.forename: Chen S
authors.initials: CS
authors.lastname: Tan
authors.forename: R Philip
authors.initials: RP
authors.lastname: Kinkel
authors.forename: Marion C
authors.initials: MC
authors.lastname: Stein
authors.forename: Raphael P
authors.initials: RP
authors.lastname: Viscidi
authors.forename: Long H
authors.initials: LH
authors.lastname: Ngo
authors.forename: Igor J
authors.initials: IJ
authors.lastname: Koralnik
mesh_terms: D000328:Adult; D000911:Antibodies, Monoclonal / Q000009:adverse effects* / Q000627:therapeutic use; D061067:Antibodies, Monoclonal, Humanized; D000914:Antibodies, Viral / Q000097:blood; D004279:DNA, Viral / Q000097:blood; D005260:Female; D006801:Humans; D039441:Integrin alpha4 / Q000276:immunology*; D007577:JC Virus / Q000235:genetics / Q000276:immunology / Q000302:isolation & purification / Q000502:physiology*; D007968:Leukoencephalopathy, Progressive Multifocal / Q000139:chemically induced*; D008297:Male; D008875:Middle Aged; D020529:Multiple Sclerosis, Relapsing-Remitting / Q000150:complications / Q000188:drug therapy*; D000069442:Natalizumab; D010865:Pilot Projects; D014556:Urine / Q000821:virology; D019562:Viral Load; D014766:Viremia / Q000175:diagnosis; D014775:Virus Activation / Q000187:drug effects*; D055815:Young Adult
chemical_list: D000911:Antibodies, Monoclonal; D061067:Antibodies, Monoclonal, Humanized; D000914:Antibodies, Viral; D004279:DNA, Viral; D000069442:Natalizumab; D039441:Integrin alpha4