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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 HLAB27 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.
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 HLAB27 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. 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.