title: Spontaneous clearance of chronic hepatitis C virus infection is associated with appearance of neutralizing antibodies and reversal of T-cell exhaustion.
abstract: BACKGROUND
  Hepatitis C virus (HCV) readily establishes chronic infection with exhaustion of HCV-specific T cells and escape from neutralizing antibodies. Spontaneous recovery from chronic infection is rare and has never to our knowledge been studied immunologically.
  
  
  METHODS
  We prospectively studied, from prior to infection through >2 years of follow-up, cytokines, HCV-specific T cells, and antibodies, as well as viral sequence evolution in a white male who spontaneously cleared HCV genotype 1a after 65 weeks.
  
  
  RESULTS
  Significant alanine aminotransferase and plasma cytokine elevation and broad HCV-specific T-cell responses did not result in HCV clearance in the acute phase. Frequency and effector function of HCV-specific T cells decreased thereafter, and HCV titers stabilized as is typical for the chronic phase. HCV clearance after 65 weeks followed the appearance of neutralizing antibodies at week 48 and was associated with reversal of HCV-specific T-cell exhaustion, as evidenced by reduced programmed death-1 (PD-1) expression and improved T-cell function. Clearance occurred without inflammation or superinfection with hepatitis B virus, human cytomegalovirus virus, influenza, and Epstein-Barr virus.
  
  
  CONCLUSIONS
  T-cell exhaustion is reversible at least in the first 2 years of chronic HCV infection, and this reversion in conjunction with neutralizing antibodies may clear HCV. These findings are relevant for immunotherapy of chronic infections.
authors.affiliation: Immunology Section, Liver Diseases Branch, National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK), National Institutes of Health, Department of Health and Human Services (DHHS), Bethesda, MD, USA.
authors.forename: Sukanya
authors.initials: S
authors.lastname: Raghuraman
authors.forename: Heiyoung
authors.initials: H
authors.lastname: Park
authors.forename: William O
authors.initials: WO
authors.lastname: Osburn
authors.forename: Emily
authors.initials: E
authors.lastname: Winkelstein
authors.forename: Brian R
authors.initials: BR
authors.lastname: Edlin
authors.forename: Barbara
authors.initials: B
authors.lastname: Rehermann
mesh_terms: D000293:Adolescent; D000328:Adult; D057134:Antibodies, Neutralizing / Q000097:blood*; D016207:Cytokines / Q000097:blood*; D016174:Hepacivirus / Q000235:genetics / Q000276:immunology; D018937:Hepatitis C Antibodies / Q000097:blood; D019698:Hepatitis C, Chronic / Q000276:immunology*; D006801:Humans; D007371:Interferon-gamma / Q000097:blood; D008137:Longitudinal Studies; D008297:Male; D061026:Programmed Cell Death 1 Receptor / Q000378:metabolism; D011446:Prospective Studies; D020127:Recovery of Function / Q000276:immunology*; D012075:Remission, Spontaneous; D017422:Sequence Analysis, DNA; D013601:T-Lymphocytes / Q000276:immunology*; D019562:Viral Load; D055815:Young Adult
chemical_list: D057134:Antibodies, Neutralizing; D016207:Cytokines; D018937:Hepatitis C Antibodies; D061026:Programmed Cell Death 1 Receptor; D007371:Interferon-gamma