Hepatitis C virus (HCV) is the etiologic agent of non-A, non-B hepatitis. HCV is now the most common cause of chronic liver disease in the United States and has surpassed alcoholic liver disease as the most common indication for liver transplantation in North America. An estimated 1.8% of all Americans are infected with a higher percentage among African Americans (AA). A hallmark of the disease is its predilection to become chronic with up to 85% of those exposed having chronic infection. The UTHSC Memphis Hepatitis C Cooperative Research Center was established to support clinical and basic research to understand the basis for chronic disease in HCV infection and response to therapy in clinically infected patients. The population of the greater Memphis area is 55% AA within which there is a significant problem with chronic HCV infection. The well documented poor response rate of AA to combination therapy exacerbates the obvious health problem of chronic HCV in this region. The primary research goal of the Memphis Hepatitis C Cooperative Research Center and this proposal is to understand why AA are more susceptible to chronic infection and why their response rate to combination therapy is only 50% or less of that for non AA patients. The research proposed for Project #1 derives from intriguing preliminary results on the association of chronic hepatitis C and poor response to therapy in AA to HLA-DRB1*11 alleles. The frequency of inheritance of this allele among chronically infected AA is approximately three times the expected frequency among the general AA population in the Midsouth. DRB1 * 13 alleles, however, appear to be associated with successful responses to therapy. The proposed research program for the Center includes two projects, an administrative core, and a clinical core Project #1 will determine how HLA class dependent immune regulation and T cell specificities affect differences in immune responses to HCV and response to therapy in AA compared to non AA patients. The aims are 1) Determine HLA and immune response differences that correlate with chronic HCV infection and differences in response to therapy between AA and CAU patients. 2) Identify HLA class II-dependent immune regulation that limits or suppresses HCV immune responses in chronically infected individuals and reduces the response to therapy in AA compared to CAU. 3) Identify T cell peptide epitopes for DR11, DR13, and DR15 presented HCV proteins. 4) Determine and compare T Cell receptor structures for HCV-specific T cells in peripheral blood and liver of chronic hepatitis C patients.