In this application for an Ancillary Center of the Virahep-C trial, we will focus on defining the role of the cellular immune responses in determining resistance to antiviral therapy in chronic HCV infection. Why HCV persists with great efficiency in a high proportion of patients receiving therapy, particularly in African-Americans, is a crucial issue that remains to be explained. We hypothesize that quantitative and qualitative differences in HCV-specific CD4+ and CD8+ T cell responses exist in patients prior to therapy that will correlate with response. Specifically, patients with higher frequencies of circulating HCV-specific Th1 effector cells will clear HCV at an increased rate as compared to patients with lower Th1 frequencies or relatively higher frequencies of HCV-specific Th2-producing cells. Therapy may """"""""reconstitute"""""""" a Thl phenotype in patients who successfully clear the virus. In order to test the hypothesis that CD8+ T cell responses are quantitatively weaker and/or more narrowly targeted in African Americans, we will comprehensively determine responses to pools of overlapping peptides that span the entire HCV genome. We also propose to test the notion that mutations in immunodominant CD8+ T cell epitopes contribute to viral escape from immune recognition. By longitudinally examining HLA class I-restricted responses in treated patients, we can determine whether these responses expand or become more narrowly focused and how these dynamic responses correlate to longterm outcome of antiviral therapy. To test these hypotheses we will utilize highly sensitive assays which detect cytokine production at the single cell level and which do not require in vitro cell expansion of lymphocytes collected ex vivo from prospectively studied patients receiving therapy. A more thorough understanding of the immune correlates of viral clearance following antiviral therapy is needed to predict which patients will respond and in order to develop novel immunomodulatory approaches to therapy. Using highly sensitive assays, we will focus on the quantitative and kinetic aspects of successful HCV-specific CD4+ and CD8+ T cell responses to create a conceptual paradigm that can be examined by further experiments to facilitate development of vaccines and immunotherapies.
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