title: Spontaneous control of HCV is associated with expression of HLA-B 57 and preservation of targeted epitopes.
abstract: OBJECTIVE
  HLA class I alleles are linked to spontaneous control of hepatitis C virus (HCV) and human immunodeficiency virus-1, but for HCV the roles of particular alleles and corresponding CD8(+) T-cell responses remain incompletely defined. We aimed to determine the correlations between these alleles and natural outcomes of HCV and determine associated key T-cell responses.
  
  
  METHODS
  In a cohort of HCV individuals, we determined HLA class I alleles, HCV outcomes, T-cell responses, and examined sequence data for mutational changes within key epitopes.
  
  
  RESULTS
  Carriage of HLA-B 57 was associated with a higher rate of viral clearance (risk ratio = 2.0; 95% confidence interval: 1.2-3.4), while HLA-B 08 was associated with a lower rate (risk ratio = 0.34; 95% confidence interval: 0.1-0.9]. Two HLA-B 57-restricted T-cell epitopes were targeted in spontaneous clearance; subjects with chronic viremia expressing HLA-B 57 harbored HCV strains with a high frequency of mutations in key residues. HLA-B 57-mediated escape was supported by diminished immune recognition of these variants and acute HCV infection revealing viral evolution toward less recognized variants. Analysis of a genotype 1b strain from a single-source HCV outbreak in which HLA-B 57 was not protective revealed sequence variations that interfere with immunogenicity, thereby preventing HLA-B 57-mediated immune pressure.
  
  
  CONCLUSIONS
  Our data indicate a role of HLA-B 57-restricted CD8(+) T-cell responses in mediating spontaneous clearance and evolution in HCV infection, and viral strains containing epitope variants that are less recognized abrogate the protective effects of HLA-B 57. The finding that HLA-B 57-mediated antiviral immunity is associated with control of both human immunodeficiency virus-1 and HCV suggests a common shared mechanism of a successful immune response against persistent viruses.
authors.affiliation: Division of Infectious Diseases, Massachusetts General Hospital, Harvard Medical School, GRB-504, Boston, Massachusetts 02114, USA. akim1@partners.org
authors.forename: Arthur Y
authors.initials: AY
authors.lastname: Kim
authors.forename: Thomas
authors.initials: T
authors.lastname: Kuntzen
authors.forename: Joerg
authors.initials: J
authors.lastname: Timm
authors.forename: Brian E
authors.initials: BE
authors.lastname: Nolan
authors.forename: Melanie A
authors.initials: MA
authors.lastname: Baca
authors.forename: Laura L
authors.initials: LL
authors.lastname: Reyor
authors.forename: Andrew C
authors.initials: AC
authors.lastname: Berical
authors.forename: Andrea J
authors.initials: AJ
authors.lastname: Feller
authors.forename: Kristin L
authors.initials: KL
authors.lastname: Johnson
authors.forename: Julian
authors.initials: J
authors.lastname: Schulze zur Wiesch
authors.forename: Gregory K
authors.initials: GK
authors.lastname: Robbins
authors.forename: Raymond T
authors.initials: RT
authors.lastname: Chung
authors.forename: Bruce D
authors.initials: BD
authors.lastname: Walker
authors.forename: Mary
authors.initials: M
authors.lastname: Carrington
authors.forename: Todd M
authors.initials: TM
authors.lastname: Allen
authors.forename: Georg M
authors.initials: GM
authors.lastname: Lauer
mesh_terms: D000368:Aged; D000369:Aged, 80 and over; D018414:CD8-Positive T-Lymphocytes / Q000276:immunology; D015331:Cohort Studies; D000939:Epitopes / Q000276:immunology; D005260:Female; D015235:HLA-B Antigens / Q000235:genetics / Q000276:immunology*; D016174:Hepacivirus / Q000235:genetics / Q000276:immunology*; D019698:Hepatitis C, Chronic / Q000276:immunology* / Q000821:virology*; D006801:Humans; D008297:Male; D008875:Middle Aged; D009154:Mutation
chemical_list: D000939:Epitopes; D015235:HLA-B Antigens; C103707:HLA-B57 antigen