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.

Public Health Relevance

Hepatitis C virus (HBV) infects about 3% of the world population and is a major indicator for liver transplantation. There is no vaccine available. HCV alters host lipid metabolic pathways for establishing infectious process. This proposal focuses on the role of lipids in the HCV maturation and secretion from infected hepatocytes.

Agency
National Institute of Health (NIH)
Institute
National Institute of Allergy and Infectious Diseases (NIAID)
Type
High Priority, Short Term Project Award (R56)
Project #
2R56AI085087-05
Application #
8914210
Study Section
Special Emphasis Panel (ZRG1-IDM-U (02))
Program Officer
Koshy, Rajen
Project Start
2009-12-01
Project End
2015-07-31
Budget Start
2014-08-27
Budget End
2015-07-31
Support Year
5
Fiscal Year
2014
Total Cost
$387,500
Indirect Cost
$137,500
Name
University of California San Diego
Department
Internal Medicine/Medicine
Type
Schools of Medicine
DUNS #
804355790
City
La Jolla
State
CA
Country
United States
Zip Code
92093