Senior Mentor: Dwain L. Thiele, M.D., Professor of Internal Medicine, Division of Digestive and Liver Diseases.

Primary Research Mentor: Geri R. Brown, M.D., Associate Professor of Internal Medicine, Division of Digestive and Liver Diseases.

Project Title: Immune Mediators of Apoptosis in Chronic Hepatitis C Infection

Brief Description: Unlike infections by other human hepatitis viruses, Hepatitis C virus (HCV) infection of healthy immunocompetent adults is persistent or prolonged in the vast majority of cases. In part, this undoubtedly relates to high rates of variability in the amino acid sequence in the hypervariable region (HVR) 1 of the HCV envelope protein which both result from immune pressure and permit "escape" from neutralizing antibodies. However, in light of the important role of cytotoxic T lymphocyte (CTL) responses in clearance of other non-cytopathic viruses, it seems likely that HCV also has evolved strategies to evade human CTL responses. Binding of the HCV core protein to the lymphotoxin receptor (LT R) and interference with LT R signaling has been reported . Thus, interference with signaling through the LT R or other members of the TNFR family of receptors is one possible mechanism whereby there is evasion of the human CTL responses. In addition, preliminary studies indicate that there is up regulation of expression of protease inhibitor 9 (PI9), a serpin inhibitor of the human CTL effector molecule, granzyme B, in human hepatoma cells infected in vitro with a Hepatitis C replicon. We propose to study whether, during chronic HCV infection, there is evidence of enhanced expression in the liver of PI9 or other serpins that may block CTL killing of HCV infected hepatocytes or suppressed expression of the TNFR1, TNFR1, LT R and Fas family of "death" receptors that also may be important in immune clearance of HCV infected cells. Quantitative real-time RT-PCR mRNA assays for assessing levels of expression of these genes will be developed and used to assess expression in liver biopsy specimens from patients with chronic hepatitis C or with other forms of liver disease. Mono-specific antibodies for PI9 will also be used to excess levels of PI9 protein expression in HCV infected versus control liver specimens.