Hepatitis B virus (HBV) is a human hepatotropic virus which is carried by approximately 200 million people worldwide. Chronic active hepatitis and liver cirrhosis are major causes of mortality, and chronic infection by HBV is closely associated with an increased risk of primary hepatocellular carcinoma, one of the most common cancers in the world. An understanding of the biology of this virus would elucidate the mechanisms of viral pathogenesis and identify potential therapeutic approaches for this very common liver cancer. Since the 3.5 kb genomic transcript of HBV not only encodes the core protein and the reverse transcriptase, but also serves as a template for HBV replication, it is very important to elucidate the mechanisms for the control of its expression. In this proposal we will focus our study on the characterization of a strong and liver-specific core enhancer in the HBV genome that we recently identified and identification of other HBV sequences that may participate in the control of core gene expression. We will: 1. localize the functional motifs of the liver-specific HBV core enhancer. 2. study by in vitro analysis of the mechanisms for the liver-specific core enhancer activity. 3. determine whether core gene expression is developmentally regulated. 4. determine whether core gene expression is affected by the levels of sterol. 5. determine whether other sequences in the HBV genome also participate in the regulation of core gene expression. It has been suggested that HBV-encoded X protein plays a regulatory role in the life cycle and tumorigenesis of HBV. Anti-X antibodies have been detected in HBV-infected patient sera and X protein has been shown to transactivate the regulatory sequences of several viral and cellular genes. The significance of these findings in relation to HBV infection, however, remains speculative. To elucidate the mechanisms of X protein transactivation as a first step to understand its role in HBV infection, we will: 1. identify the DNA sequences that respond to X protein transactivation; 2. characterize the domains in X proteins that facilitate its transactivation functions.
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