Abstract

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.

Public Health Relevance

Hepatitis C virus (HBV) infects about 3% of the world population and is a major indicator for liver transplantation. 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.

  Funding Agency

Agency
National Institute of Health (NIH)
Institute
National Institute of Allergy and Infectious Diseases (NIAID)
Type
Research Project (R01)
Project #
5R01AI085087-07
Application #
9246400
Study Section
Hepatobiliary Pathophysiology Study Section (HBPP)
Program Officer
Koshy, Rajen
Project Start
2010-07-01
Project End
2019-03-31
Budget Start
2017-04-01
Budget End
2018-03-31
Support Year
7
Fiscal Year
2017
Total Cost
Indirect Cost

  Institution

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

  Publications

Kim, Seong-Jun; Ahn, Dae-Gyun; Syed, Gulam H et al. (2018) The essential role of mitochondrial dynamics in antiviral immunity. Mitochondrion 41:21-27
Kim, Seong-Jun; Jang, Jae Young; Kim, Eun-Jung et al. (2017) Ginsenoside Rg3 restores hepatitis C virus-induced aberrant mitochondrial dynamics and inhibits virus propagation. Hepatology 66:758-771
Syed, Gulam H; Khan, Mohsin; Yang, Song et al. (2017) Hepatitis C Virus Lipoviroparticles Assemble in the Endoplasmic Reticulum (ER) and Bud off from the ER to the Golgi Compartment in COPII Vesicles. J Virol 91:
Khan, Mohsin; Syed, Gulam Hussain; Kim, Seong-Jun et al. (2015) Mitochondrial dynamics and viral infections: A close nexus. Biochim Biophys Acta 1853:2822-33
Till, Andreas; Saito, Rintaro; Merkurjev, Daria et al. (2015) Evolutionary trends and functional anatomy of the human expanded autophagy network. Autophagy 11:1652-67
Slagle, Betty L; Andrisani, Ourania M; Bouchard, Michael J et al. (2015) Technical standards for hepatitis B virus X protein (HBx) research. Hepatology 61:1416-24
Kim, Seong-Jun; Syed, Gulam H; Khan, Mohsin et al. (2014) Hepatitis C virus triggers mitochondrial fission and attenuates apoptosis to promote viral persistence. Proc Natl Acad Sci U S A 111:6413-8
Syed, Gulam Hussain; Tang, Huihui; Khan, Mohsin et al. (2014) Hepatitis C virus stimulates low-density lipoprotein receptor expression to facilitate viral propagation. J Virol 88:2519-29
Kim, Seong-Jun; Syed, Gulam H; Siddiqui, Aleem (2013) Hepatitis C virus induces the mitochondrial translocation of Parkin and subsequent mitophagy. PLoS Pathog 9:e1003285
Bishé, Bryan; Syed, Gulam H; Field, Seth J et al. (2012) Role of phosphatidylinositol 4-phosphate (PI4P) and its binding protein GOLPH3 in hepatitis C virus secretion. J Biol Chem 287:27637-47

Showing the most recent 10 out of 14 publications