Project Description: Chronic hepatitis C virus (HCV) infection is a major risk factor for the development of hepatocellular carcinoma (HCC) worldwide. The mechanisms of HCV persistence and subsequent carcinogenesis are not well understood, but most likely involve viral evasion of host immune surveillance. Induction of type 1 interferons (IFNs) and apoptosis represent the two major immediate protective responses of mammalian cells following viral infections, and are regulated by IFN-regulatory factor-3 (IRF-3), a transcription factor that is also known to function as a tumor suppressor in vivo.

Cellular activation of IRF-3 is initiated mainly through the recognition of viral double-stranded (ds) RNA by the membrane-bound Toll-like receptor 3 (TLR3) and/or a cytoplasmic RNA helicase, retinoic acid-inducible gene I (RIG-I). Although these pathways have been characterized in fibroblasts, epithelial cells, and immune cells, little is known regarding their roles in host responses to HCV infection in hepatocytes, the major target of HCV in vivo. Intriguingly, our recent results indicated that HCV has evolved to disrupt activation of IRF-3 through these pathways, by mediating proteolysis of cellular substrates with its serine protease, NS3/4A. Our long-term goal is to elucidate the relative roles of these dsRNA signaling pathways in hepatocellular control of HCV infection and how HCV regulates host responses initiated through these pathways and causes chronic infections and ultimately HCC. Our aims are to: 1. Determine the contribution of TLR3 and RIG-I to triggering IRF-3 activation in hepatocytes following HCV infection. 2. Determine whether TLR3 and/or RIG-I signaling act to limit HCV replication. 3. Determine whether HCV NS3/4A regulates cellular apoptosis response during viral infection.