Hepatitis C virus (HCV) chronically infects approximately 4 million people in the United States and 170 million people worldwide, posing a major global health problem. HCV infection results in chronic hepatitis, fibrosis/cirrhosis, and hepatocellular carcinoma. HCV is classified as the Hepacivirus genus in the Flaviviridae family. It is an enveloped RNA virus containing a single-stranded and positive sense RNA genome of 9.6 kb, which encodes a large polyprotein precursor of 3,000 amino acids. Over the years, we have made significant contributions to current knowledge regarding the roles of HCVcis-acting RNA elements and viral and cellular proteins in HCV replication and production. We are among the first to develop a robust HCV production system in cell culture. More recently, we have demonstrated that the cellular protein apolipoprotein E is a structural component anchored on the HCV envelope and has dual functions in HCV infection and assembly via specific interactions with NS5A and binding to the cell surface heparan sulfate, respectively. We have also demonstrated that HSPGs and syndecan-1 are major receptors for HCV attachment, the very first step of HCV infection. In coming years, our overall objective is to combine reverse genetic, biochemical, cell biological, proteomic, and transgenic approaches toward a thorough understanding of the molecular mechanisms of HCV infection, replication, virion assembly, virus-host interaction, and molecular pathogenesis. Specifically, our research programs include: 1) defining the roles of viral and cellular proteins in HCV infection, replication, and assembly; 2) developing small animal models of HCV infection, replication, pathogenesis, and carcinogenesis; 3) illustrating virus-host interactions in vitro and in vivo; 4) understanding the molecular bases underlying the HCV-induced carcinogenesis and profiling hepatic cancer stem cells; 5) identifying novel targets and antiviral drugs for treatment of hepatitis C; 6) developing effective HCV vaccines; and 7) determining the underlying molecular mechanism of HCV and HIV interaction in cell culture and in vivo. Additionally, we are interested in molecular genetic analysis of other RNA viruses, including hepatitis E virus, West-Nile virus, Dengue Virus, and respiratory viruses such as influenza viruses and respiratory syncytial virus.