HEPATITIS C VIRUS MECHANISMS OF LIVER INJURY--EFFECTS OF THERAPY IN HUMANS

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Current experimental therapies for hepatitis C virus includes ribavirin and alpha-interferon; however, the responses to these therapies are variable. The factors determining the efficacy of the therapies are not known. The finding described in Project I that the HCV core protein interacts with members of tumor necrosis factor receptor (TNFR) family provides a potential basis for determining the efficacy of these therapies in different patients. This project will utilize abundant clinical resources available at USC medical facilities to examine four groups of patients: (1) patients with HCV infection and elevated serum aminotransferase (ALT) level; (2) patients treated with ribavirin; (3) patients treated with alpha-interferon; (4) patients coinfected with HIV and HCV. Liver biopsy specimens derived from these patients will be examined for the expression of various TNFRs, including TNFR I, TNFR II, lymphotoxin-beta receptor and Fas, CD30 and various HCV viral antigens. They will also be examined with respect to the lymphocyte subsets. Sera from these patients will be examined for HCV genotype and RNA level, and the possible presence of soluble CD30 and TNFR. These immunological parameters will be correlated with the patients' clinical status, including ALT level, responsiveness to interferon or ribavirin therapy. This study is linked closely with Project I, and provides clinical confirmation for the in vitro studies proposed in Project I. These studies may form the conceptual basis for the next generation of therapies for hepatitis C virus, which is one of the major goals of the proposed Hepatitis C Cooperative Research Centers. Furthermore, the experience of the P.I. for this project will enable close cooperation with other potential Hepatitis C Research Centers in the country.