Mechanisms of T cell dysfunction in Hepatitis C virus persistence

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DESCRIPTION (provided by applicant): Henry Radziewicz is a highly motivated scientist at Emory University with a specialty in Infectious Diseases Medicine, whose overall goal is to develop an independent scientific career with a research program focused on understanding the pathogenesis of chronic viral infections such as hepatitis C virus (HCV). Why does the adaptive immune response to HCV fail in the majority of infected persons? His immediate goal is to receive funding through a research career award (K08) that will enable sufficient protected time for didactics and research to enable this development. His long-term goal is to discover and test better treatments of chronic viral illness with the improved understanding of their pathogenesis. HCV infects 150-200 million persons and causes chronic hepatitis, cirrhosis, and hepatocellular carcinoma. It has become the major cause of liver transplantation in the United States. Current therapies for HCV are very difficulty to tolerate due to disabling side-effects, require prolonged treatment, and are only successful in approximately half of treated patients for the major genotype in the US. Better therapies are needed. Recently, several new members of the B7/CD28 family of co-inhibitory molecules have been discovered, and may play important roles in modulating the immune responses to chronic viral infections. One pair of molecules, PD-1 and its ligand PD-L1 has demonstrated a critical role in the immune response to chronic murine LCMV infection. Blockade of PD-1/PD-L1 enhanced the response of exhausted T cells in this model, and treated mice were able to clear infection from serum, liver, and lung. We hypothesize that an inability to clear HCV viremia in the majority of infected patients is due to overexpression of the PD-1/PD-L1 co-inhibitory system. In conjunction with a research career award, Henry would like to evaluate this system in humans with chronic HCV, and to test if inhibiting this system improves the function of HCV specific CD8+ T cells. Guided by top scientists, Arash Grakoui and Rafi Ahmed, Henry's proposed 4-year program will include one year of didactics in basic immunology and signal transduction, followed by three lab-based, research concentrated years. Emory University is committed to help Henry reach his goal of becoming a top scientist, and the environment at Emory and the Vaccine Research Center is a wonderful environment for a young scientist to flourish.