Role of Lipids in Hepatitis C Virus Maturation

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 DESCRIPTION (provided by applicant): Chronic Hepatitis C virus infections affect about 170 million people worldwide and constitute a significant risk factor for fibrosis, steatosis and hepatocellular carcinoma (HCC). HCV infections are a major indicator for liver transplantation. Here, we propose to characterize the role of lipids in virion morphogenesis mostly focusing on maturation and secretion from infected hepatocytes. In the previous grant we had identified and characterized the role of several lipids and lipid interacting proteins in affecting HCV secretion. HCV maturation/secretions through the Golgi network is believed to occur in association with very low-density lipoprotein (VLDL) assembly and secretion. VLDL transport occurs in specialized VLDL transport vesicles (VTVs). We propose to characterize the transport of HCV-associated VTVs across the Golgi network using the established biochemical fractionation procedures for isolating VTVs. A newly described in vitro budding assay for the post- Golgi VTV transport will be examined. Characterization of VTVs in HCV infected cells containing HCV virions components is of fundamental importance to the understating the process of HCV secretion. We also propose to determine the functional importance of factors that affect Golgi transport of large cargos such as VTVs in HCV maturation. In this context, several proteins including a phosphatidylinosito-4 phosphate (PI4P)- interacting protein Arfaptin shown to affect large cargos in the trans-Golgi network will be characterized for their role in HCV-VTV transport. These studies will reveal unique insight into the mechanisms of HCV maturation, secretion and egress and will serve as a model for other RNA viruses. The results of this study will open new avenues for therapeutic design of cellular targets affecting the HCV secretory pathway.