The basis of chronic infection following exposure to hepatitis C virus (HCV) infection is unexplained. One factor may be the low frequency and immature phenotype of virus-specific CD8 ؉ T cells. The role of CD4 ؉ CD25 ؉ T regulatory (T reg ) cells in priming and expanding virus-specific CD8 ؉ T cells was investigated. Twenty HLA-A2-positive patients with persistent HCV infection and 46 healthy controls were studied. Virusspecific CD8؉ T-cell proliferation and gamma interferon (IFN-␥) frequency were analyzed with/without depletion of T reg cells, using peptides derived from HCV, Epstein-Barr virus (EBV), and cytomegalovirus (CMV). CD4؉ CD25 ؉ T reg cells inhibited anti-CD3/CD28 CD8 ؉ T-cell proliferation and perforin expression. Depletion of CD4؉ CD25 ؉ T reg cells from chronic HCV patients in vitro increased HCV and EBV peptidedriven expansion (P ‫؍‬ 0.0005 and P ‫؍‬ 0.002, respectively) and also the number of HCV-and EBV-specific IFN-␥-expressing CD8 ؉ T cells. Although stimulated CD8 ؉ T cells expressed receptors for transforming growth factor beta and interleukin-10, the presence of antibody to transforming growth factor beta and interleukin-10 had no effect on the suppressive effect of CD4 ؉ CD25 ؉ regulatory T cells on CD8 ؉ T-cell proliferation. In conclusion, marked CD4 ؉ CD25 ؉ regulatory T-cell activity is present in patients with chronic HCV infection, which may contribute to weak HCV-specific CD8 ؉ T-cell responses and viral persistence.

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. T he hepatitis C virus (HCV) is a small positivestranded RNA virus within the Flaviviridae family that persists in 70% of infected individuals. Growing evidence suggests that the cellular host immune response against HCV plays an important role in the outcome of infection. Indeed, viral clearance is temporarily associated with sustained HCV-specific CD4ϩ and CD8ϩ T cell responses that accumulate in the infected liver. [1][2][3] In addition, the important antiviral role of virusspecific CD8ϩ T cells has recently been directly demonstrated by CD8ϩ cell depletion studies in chimpanzees. 4 The mechanisms that lead to the failure of the virus-specific T cell response and the persistence of HCV in most patients are still not well understood. 5 Several different pathways, such as a primary failure to induce T cells, functional exhaustion, or the emergence of viral escape mutations, have been discussed. [5][6][7] Indeed, a growing body of evidence suggests that T cell escape mutations develop early during acute HCV infection and that they remain fixed in the circulating quasispecies for several years. [8][9][10][11][12][13][14][15][16][17] However, the development of escape mutations during HCV infection is not universal. For example, viral clearance can occur with minimal epitope variation before From the

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