This subproject is one of many research subprojects utilizing theresources provided by a Center grant funded by NIH/NCRR. The subproject andinvestigator (PI) may have received primary funding from another NIH source,and thus could be represented in other CRISP entries. The institution listed isfor the Center, which is not necessarily the institution for the investigator.Hepatitis C virus (HCV) infection is a growing public health problem affecting 170 million people worldwide (~3 million in the United States). While twenty percent of patients infected with HCV are able to clear the infection after several months, the majority of patients become chronic carriers who, in addition to being the source for most new infections, can progress to chronic active hepatitis with cirrhosis and/or hepatocellular carcinoma (HCC). These clinical sequelae of HCV infection now comprise the leading indication for liver transplantation in the United States and account for significant morbidity and mortality each year. However, despite its potentially grave clinical consequences, the only licensed therapy for chronic hepatitis C infection is alpha interferon (IFNa), either alone or in combination with the nucleoside analog ribavirin. This therapy is expensive, associated with poor response rates, and laden with significant side effects. The paucity of efficacious anti-HCV therapeutic options highlights the need for effective interventions aimed at augmenting or supplementing the natural immune response and that alone or in concert with drug therapy can prevent the detrimental consequences of HCV infection. Development of such successful intervention strategies requires a thorough understanding of the host determinants of infection resolution and this proposal is designed to provide the framework for improving our current understanding of such host factors. Our working hypothesis is that the reciprocal and cognate interaction between CD4+ T cells and antigen presenting cells is insufficient early in HCV infection and that the failure to generate a protective neutralizing anti-HCV response during the acute stages of infection is an immediate result of this inadequacy. We specifically rigorously analyzed the peripheral and intrahepatic memory cellular immune response in experimental chimpanzees that are chronically infected or have acutely resolved HCV infection as well as in human patients infected with HCV.
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