Model systems to study hepatitis C virus tropism for the liver. (360G-Wellcome-078044_Z_05_Z)

Studies on Hepatitis C virus (HCV) cell entry and tropism have largely been ignored due to technical limitations in our inability to propagate HCV in cell culture. However, the development of infectious retrovirus pseudotypes bearing HCV glycoproteins (HCVpp) has allowed studies to analyze the cellular molecules required for HCV-cell entry. More recently, we and others have shown the JFH strain of HCV is able to assemble and release infectious particles in cell culture (HCVcc). This proposal will compare the receptor usage and tropism of HCVpp and HCVcc and will aim to select the most appropriate system to study the mechanism(s) of viral entry. Our current research shows that HCVpp and HCVcc infectivity is dependent on host cell expression of CD81 and additional unidentified liver specific molecule(s). We will define the role(s) of CD81, scavenger receptor B I and associated cellular proteins in HCV attachment and internalization into primary hepatocyte and hepatoma derived cell lines. We hypothesize that liver specific molecule(s) modulate the receptor activity of CD81 and identification of CD81-protein complexes within permissive cells will elucidate the HCV-protein interactions required for virus infection. Understanding the receptor requirements for HCV entry will aid in the design of small animal models for HCV infection.