title: Synergism of tapasin and human leukocyte antigens in resolving hepatitis C virus infection.
abstract: CD8+ T-cell responses to hepatitis C virus (HCV) are important in generating a successful immune response and spontaneously clearing infection. Human leukocyte antigen (HLA) class I presents viral peptides to CD8+ T cells to permit detection of infected cells, and tapasin is an important component of the peptide loading complex for HLA class I. We sought to determine if tapasin polymorphisms affected the outcome of HCV infection. Patients with resolved or chronic HCV infection were genotyped for the known G/C coding polymorphism in exon 4 of the tapasin gene. In a European, but not a US, Caucasian population, the tapasin G allele was significantly associated with the outcome of HCV infection, being found in 82.5% of resolvers versus 71.3% of persistently infected individuals (P = 0.02, odds ratio [OR] = 1.90 95% confidence interval [CI] = 1.11-3.23). This was more marked at the HLA-B locus at which heterozygosity of both tapasin and HLA-B was protective (P < 0.03). Individuals with an HLA-B allele with an aspartate at residue 114 and the tapasin G allele were more likely to spontaneously resolve HCV infection (P < 0.00003, OR = 3.2 95% CI = 1.6-6.6). Additionally, individuals with chronic HCV and the combination of an HLA-B allele with an aspartate at residue 114 and the tapasin G allele also had stronger CD8+ T-cell responses (P = 0.02, OR = 2.58, 95% CI-1.05-6.5).
  
  
  CONCLUSIONS
  Tapasin alleles contribute to the outcome of HCV infection by synergizing with polymorphisms at HLA-B in a population-specific manner. This polymorphism may be relevant for peptide vaccination strategies against HCV infection.
authors.affiliation: Clinical and Experimental Sciences, Faculty of Medicine, University of Southampton, UK.
authors.forename: Shirin
authors.initials: S
authors.lastname: Ashraf
authors.forename: Katja
authors.initials: K
authors.lastname: Nitschke
authors.forename: Usama M
authors.initials: UM
authors.lastname: Warshow
authors.forename: Collin R
authors.initials: CR
authors.lastname: Brooks
authors.forename: Arthur Y
authors.initials: AY
authors.lastname: Kim
authors.forename: Georg M
authors.initials: GM
authors.lastname: Lauer
authors.forename: Theresa J
authors.initials: TJ
authors.lastname: Hydes
authors.forename: Matthew E
authors.initials: ME
authors.lastname: Cramp
authors.forename: Graeme
authors.initials: G
authors.lastname: Alexander
authors.forename: Ann-Margaret
authors.initials: AM
authors.lastname: Little
authors.forename: Robert
authors.initials: R
authors.lastname: Thimme
authors.forename: Christoph
authors.initials: C
authors.lastname: Neumann-Haefelin
authors.forename: Salim I
authors.initials: SI
authors.lastname: Khakoo
mesh_terms: D000328:Adult; D000483:Alleles; D000998:Antiviral Agents / Q000627:therapeutic use; D015331:Cohort Studies; D005260:Female; D006680:HLA Antigens / Q000235:genetics / Q000502:physiology*; D015235:HLA-B Antigens / Q000235:genetics / Q000502:physiology; D016174:Hepacivirus; D006526:Hepatitis C / Q000188:drug therapy* / Q000503:physiopathology*; D006801:Humans; D016015:Logistic Models; D008297:Male; D026901:Membrane Transport Proteins / Q000235:genetics / Q000502:physiology*; D008875:Middle Aged; D011110:Polymorphism, Genetic / Q000235:genetics; D011379:Prognosis; D016896:Treatment Outcome
chemical_list: D000998:Antiviral Agents; D006680:HLA Antigens; D015235:HLA-B Antigens; D026901:Membrane Transport Proteins; C107762:tapasin