Role of Lipids in Hepatitis C Virus Maturation

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DESCRIPTION (provided by applicant): About 3% of world population is infected with Hepatitis C virus (HCV). HCV infection often leads to chronic hepatitis and about one third of patients develop cirrhosis and a minority of those develops hepatocellular carcinoma. The infection is also associated with fatty liver disease. HCV replicates its RNA genome within ribonucleoprotein complexes (RNP) consisting of viral and host cellular factors. One such host factor, termed oxysterol binding protein (OSBP) was identified by an affinity based approach by us. Subsequent studies revealed that OSBP was necessary for HCV secretion/release with no obvious effect on intracellular RNA replication. It belongs to group of proteins referred to as phosphatidyinosito-4 phosphate (PI4P)-interacting proteins. In this application, we focus on the investigation of OSBP and two other PI4P-interacting proteins, CERT and GOLPH3 in HCV maturation/secretion pathway. Role of Golgi kinase PKD in HCV maturation will also investigated. HCV maturation/secretion, which likely occurs in the Golgi compartment, is widely believed to occur in association with very low density lipoprotein (VLDL) particles. We propose to characterize the HCV maturation process through Golgi compartments by confocal laser microscopy and immunofluorescence in the context of OSBP and VLDL secretory pathway. VLDL particles are secreted via specialized VLDL transport vesicles (VTVs). Using an established biochemical fractionation procedure of isolation of VTVs, we propose to determine the association of HCV components with VTVs. Characterization of VTVs in HCV infected cells containing HCV virion components is of fundamental importance in understanding the HCV morphogenesis. Identification of host factors involved in this assembly/secretion process will also open new avenues for designing novel antiviral strategies. These studies will reveal unique insights into the mechanisms of HCV maturation, secretion and budding processes and provide a unique model for other RNA viruses. PUBLIC HEALTH RELEVANCE: HCV infections progresses to cirrhosis, steatosis, and liver cancer and are the leading indications for liver transplants thus representing a major public health burden. About 3% of world population is infected with HCV.