Hepatitis C virus (HCV) is a major health problem, affecting over 170 million people worldwide. Of persons acutely infected with HCV, about 15% spontaneously clear the virus. Because of limitations in experimental models and the infrequent recognition of natural acute infection, the mechanisms of viral clearance are poorly understood. There are clinical and epidemiologic clues that suggest host factors are critical. Among the factors influencing the outcome of HCV infection, the host genetic factors are thought to play a predominant role. Immunoglobulin (Ig) GM and KM allotypes[unreadable]hereditary antigenic determinants of IgG heavy chains and k-type light chains, respectively[unreadable]are associated with viral immunological properties, and thus are ideal candidate genetic systems for investigations to identify risk-conferring factors in HCV pathogenesis. We hypothesized that GM and KM allotypes may contribute to the outcome of HCV infection through their possible influence on allotype-restricted antibody responses to the viral antigens. Additionally, they may influence antibody dependent T cell cytotoxicity to HCV by their differential interaction with Fcgamma receptors (FcgammaR). GM and KM allotypes could also modulate the strategies[unreadable]Ig molecular mimicry and FcgammaR-like activity[unreadable]employed by this virus to evade host immune surveillance. To test our hypothesis, a case control study has been designed with the following specific aims: (1) to further establish the magnitude of association between the outcome of HCV infection and Ig GM and KM allotypes in African Americans; (2) to determine if GM and KM allotypes are associated with the outcome of HCV infection in Caucasians; (3) to measure the specificity and titer of the humoral immune responses to HCV antigens (core, E1,E2,NS3,NS4,NS5) and determine if the production of these antibodies is influenced by GM and KM allotypes; (4) to determine if HCV-encoded FcgammaR binds differentially with IgG molecules carrying different GM allotypes. GM and KM allotyping will be done by hemagglutination-inhibition, direct DNA sequencing, and PCR-RFLP methods. IgG antibodies to HCV antigens will be measured by an ELISA. Binding and comparative affinities of IgG molecules of different GM allotypes to HCV-FcgammaR will be monitored by surface plasmon resonance detection. Results of this investigation will advance our understanding of the role of host genetic factors in clearance and persistence of hepatitis C virus infection.