HBV replication and carcinogenesis

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DESCRIPTION (provided by applicant): 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.