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 8-10,000 deaths each year in the United States alone. Despite its grave clinical consequences (i) no vaccine exists to prevent HCV infection and (ii) the only licensed therapy (alpha interferon (IFN_), either alone or in combination with the nucleoside analog ribavirin) for chronic HCV infection 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.
Our previous work has established the importance of the memory CD4+ T cell response in HCV infection resolution and prevention of viral escape as well as confirmed the importance of intrahepatic CD8+ T cells in viral elimination. Our laboratory is now focused on four main project areas utilizing murine, human and non-human primate experimental systems: