Dominant influence of an HLA-B27 restricted CD8+ T cell response in mediating HCV clearance and evolution

Abstract

Virus‐specific CD8+ T cell responses play an important role in the natural course of infection; however, the impact of certain CD8+ T cell responses in determining clinical outcome has not been fully defined. A well‐defined cohort of women inoculated with HCV from a single source showed that HLA‐B27 has a strong association with spontaneous clearance. The immunological basis for this association is unknown. However, the finding is especially significant because HLA‐B27 has also been shown to have a protective role in HIV infection. We report the identification of an HLA‐B27 restricted hepatitis C virus (HCV)‐specific CD8+ T cell epitope that is recognized in the majority of recovered HLA‐B27 positive women. In chronically HCV‐infected individuals, analysis of the corresponding viral sequence showed a strong association between sequence variations within this epitope and expression of HLA‐B27, indicating allele‐specific selection pressure at the population level. Functional analysis in 3 chronically HCV‐infected patients showed that the emerging variant viral epitopes represent escape mutations. In conclusion, our results suggest a dominant role of HLA‐B27 in mediating spontaneous viral clearance as well as viral evolution in HCV infection and mechanistically link both associations to a dominant novel CD8+ T cell epitope. These results support the central role of virus‐specific CD8+ T cells and the genetically determined restriction of the virus‐specific T cell repertoire in HCV infection. (HEPATOLOGY 2006;43:563–572.)