• Open Access

Synergism of tapasin and human leukocyte antigens in resolving hepatitis C virus infection

Authors


  • Potential conflict of interest: Nothing to report.

  • Supported by grants from the Wellcome Trust (to S.I.K.), the Deutsche Forschungsgemeinschaft DFG (TH-719/3-1 to R.T. and NE1567/1-1 to C.N.H.) and the National Institutes of Health, grants U19 AI0663445 (to G.M.L. and A.Y.K.), R01 DA033541 (to A.Y.K.), and U19 AI082630 (to G.M.L.).

Address reprint requests to: Salim Khakoo, Faculty of Medicine, University of Southampton, Mailpoint 811, Level E South Academic Block, Southampton General Hospital, Tremona Road, Southampton, SO16 6YD, UK. E-mail: S.I.Khakoo@soton.ac.uk; fax: 023 8051 1761.

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). Conclusion: 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. (Hepatology 2013;53:881–889)

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