: Chronic hepatitis C virus (HCV) is one of the most prevalent diseases of the liver in the United States. It is associated with progressive hepatic fibrosis, cirrhosis and increased risk of hepatocellular carcinoma. Approximately 2.4 million Americans have chronic hepatitis C infection and the rate is higher among the African Americans (3.2%) than among the Caucasian population (1.5%). Distressingly, the mortality rates for hepatitis C-related cirrhosis and the incidence of hepatocellular carcinoma due to HCV appear to be increasing, and these increases are expected to disproportionably affect African Americans. This threat is magnified by the fact that African American patients have a lower rate of response to alpha interferon (IFN() based therapy compared to Caucasian, Mexican American and Asian patients. The reasons for the relative lack of response to antiviral therapy among African Americans are not clear. Therapy with IFN-( is associated with a Diphasic decline in the quantity of virus present in plasma or serum. The initial decline (phase 1) is characterized by a rapid decrease in serum HCV RNA levels in the first 24 hours and it is followed by a much more gradual decline by 48 hours onward (phase 2). Analysis by a mathematical model suggests that the acute effect of IFN-( is due to an antiviral activity that blocks virion production or release from the liver, while the slower, later decline is due to the immune removal of infected cells within the liver. However, the actual """"""""antiviral"""""""" mechanisms of IFN-( remain uncertain and an important role for enhanced clearance of virus from the serum due to the immunomodulatory actions of IFN-( cannot be excluded. This proposal seeks to understand the role of racial and host genetic factors in determining interferon response in HCV infection. Briefly stated, our hypotheses are: (1) that the rates of the HCV decline in serum and liver after IFN-( will be slower among African Americans compared to Caucasians, (2) that this difference in viral kinetics reflects differences in IFN-( induced intrahepatic and/or lymphocytic gene expression among Caucasians and African Americans, and (3) that an analysis of differences in the transcriptional responses to IFN-( and the in vitro evaluation of specific Interferon stimulated genes (ISGs) on HCV RNA replication in the replicon system between early virological responders and non-responders will lead to a better understanding of host pathways involved in the suppression of hepatitis C virus replication and the induction of a sustained virological response to therapy
