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Chronic hepatitis C virus (HCV) infection is associated with impaired proliferative, cytokine, and cytotoxic effector functions of HCV-specific CD8؉ T cells that probably contribute significantly to viral persistence. Here, we investigated the potential role of T cells with a CD4؉ CD25 ؉ regulatory phenotype in suppressing virusspecific CD8؉ T-cell proliferation during chronic HCV infection. In vitro depletion studies and coculture experiments revealed that peptide specific proliferation as well as gamma interferon production of HCVspecific CD8؉ T cells were inhibited by CD4 ؉ CD25 ؉ T cells. This inhibition was dose dependent, required direct cell-cell contact, and was independent of interleukin-10 and transforming growth factor beta. Interestingly, the T-cell-mediated suppression in chronically HCV-infected patients was not restricted to HCV-specific CD8 ؉ T cells but also to influenza virus-specific CD8 ؉ T cells. Importantly, CD4 ؉ CD25 ؉ T cells from persons recovered from HCV infection and from healthy blood donors exhibited significantly less suppressor activity. Thus, the inhibition of virus-specific CD8 ؉ T-cell proliferation was enhanced in chronically HCV-infected patients. This was associated with a higher frequency of circulating CD4 ؉ CD25؉ cells observed in this patient group. Taken together, our results suggest that chronic HCV infection leads to the expansion of CD4 ؉ CD25 ؉

360 million people are chronically infected with the human hepatitis B virus (HBV) and are consequently prone to develop liver cirrhosis and hepatocellular carcinoma. As approved therapeutic regimens-which modulate patients' antiviral defenses or inhibit the viral reverse transcriptase-are generally noncurative, strategies interfering with other HBV replication steps are required. Expanding on our demonstration that acylated peptides derived from the large HBV envelope protein block virus entry in vitro, we show their applicability to prevent HBV or woolly monkey hepatitis B virus infection in vivo, using immunodeficient urokinase-type plasminogen activator (uPA) mice repopulated with primary human or Tupaia belangeri hepatocytes. Accumulation of the peptides in the liver, their extraordinary inhibitory potency and specific mode of action permit subcutaneous delivery at very low doses. Inhibition of hepadnavirus entry thus constitutes a therapeutic approach to prevent primary HBV infection, such as after liver transplantation, and might also restrain virus spread in chronically infected patients.

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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