Role of Lipids in Hepatitis C Virus Maturation

描述（由申请人提供）：慢性丙型肝炎病毒感染影响全球约1.7亿人，是纤维化、脂肪变性和肝细胞癌（HCC）的重要危险因素。HCV感染是肝移植的主要指标。在这里，我们提出表征脂质在病毒粒子形态发生中的作用，主要集中在感染肝细胞的成熟和分泌。在之前的资助中，我们已经确定并描述了几种脂质和脂质相互作用蛋白在影响HCV分泌中的作用。

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. Here, we propose to continue these studies and focus on the role of phosphatidylinosito-4 phosphate (PI4P)-interacting proteins including ceramide transfer protein (CERT), Nir-2, and Arfaptin in affecting the secretory transport of HCV virions across the Golgi network. 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 an established biochemical fractionation procedure for isolating VTVs. Characterization of VTVs in HCV infected cells containing HCV virions components is of fundamental importance to the understating of HCV morphogenesis. We also propose to determine the functional importance of factors that affect VTVs in HCV maturation. 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.