Hepatitis B virus (HBV) is a hepatotropic virus that can cause severe liver diseases including acute and chronic hepatitis, liver cirrhosis and hepatocellular carcinoma (HCC). There are 350-400 million people in the world chronically infected by this virus, resulting in an estimated 1 million deaths every year. In the U.S., the chronic HBV carrier population is about 1.2 million and in China, the carrier population is about 100 million. Recently, we discovered that HBV could induce autophagy to enhance its DNA replication. We also found that impairing autophagy could induce the initiation but impede the progression of hepatocarcinogenesis in a mouse model. These previous studies of ours demonstrated an important role of autophagy in HBV replication and carcinogenesis. Our proposed research is to continue these novel findings to further study the interplay between HBV and its host. Specifically, we will study the molecular mechanism of HBV-induced autophagy. Our recent studies indicated that the HBV X protein could bind to the class III phosphatidylinositol-3-kinase (PI3KC3) to enhance its enzymatic activity. For that reason, we will further determine how this interaction between HBx and PI3KC3 induces autophagy. We will also investigate how autophagy enhances HBV DNA replication. We will determine whether autophagic vacuoles serve as the platform for HBV DNA replication and whether autophagy affects cellular factors that regulate HBV DNA replication. Finally, we will determine the role of autophagy in HBV-induced hepatocarcinogenesis. We will examine why impairing autophagy facilitates the initiation of hepatocarcinogenesis and yet in the mean time inhibits its progression. Our attention will be focused on the phenotypic difference of liver tumors produced in the absence and presence of autophagy, the role of tumor suppressors in hepatocarcinogenesis, and the effect of autophagy on hepatic tumor-initiating stem cells. Our proposed research will generate important information for us to understand the interaction between HBV and its host cell and lead to a better understanding of HBV replication and carcinogenesis.

Public Health Relevance

Hepatitis B virus (HBV) is an important human pathogen. There are approximately 1.2 million people in the U.S. that are chronically infected by this virus. Many of these patients will develop severe liver diseases including liver cirrhosis and liver cancer and will require liver transplantation for survival. The goal of our proposed research is to understand the interaction between HBV and hepatocytes and how that interaction affects HBV replication and the progression of liver diseases. Our research will improve our knowledge about this important pathogen and lead to the improvements of treatments for HBV patients.

Agency
National Institute of Health (NIH)
Type
Research Project (R01)
Project #
5R01CA177337-02
Application #
8721897
Study Section
Special Emphasis Panel (ZCA1)
Program Officer
Read-Connole, Elizabeth Lee
Project Start
Project End
Budget Start
Budget End
Support Year
2
Fiscal Year
2014
Total Cost
Indirect Cost
Name
University of Southern California
Department
Microbiology/Immun/Virology
Type
Schools of Medicine
DUNS #
City
Los Angeles
State
CA
Country
United States
Zip Code
90089
Ou, Jing-Hsiung James (2014) Virus control goes epigenetic. PLoS Pathog 10:e1004370