Epidemiologic studies have shown that infection with Hepatitis B virus (HBV) is a major worldwide public health problem. In areas where HBV is endemic, the chronic infection rate reaches 5-10% or more in the general population. Several lines of evidence suggest that persistence of HBV infection is related to development of hepatocellular carcinoma (HCC). Many patients with HCC are also HBV carriers. The published studies do not prove that HBV is oncogenic. The finding of HBV DNA in all carcinomas and the presence of integrated HBV DNA in many carcinomas is highly suggestive that HBV is oncogenic or stimulates oncogenesis. In the studies outlined, we will elucidate biochemical and molecular pathways by which HBV may cause hepatitis in primates including humans. These novel studies will make use of molecular cloning to analyze in vivo HBV transcription in different hepatoma cell lines (e.g., PLC/PRF/5, Hep3B) as well as in the liver of chronically infected chimpanzees. In addition, we will use cell free in vitro transcription of cloned HBV genomes to identify different control signals present in the viral genome which regulates initiation, polyadenylation and the splicing processing involved during HBV mRNA biogenesis. Characterization of in vivo and in vitro HBV transcription will provide new information important in establishing the basic features and identities of different viral RNAs associated with oncogenic and chronic HBV infections. Since HBV has a narrow host range and has not been replicated in tissue culture, these studies will greatly enhance our understanding of the role of the HBV gene expression and regulation under abnormal physiologic or pathologial conditions, such as persistent HBV infection and chronic liver disease. In this light, we will also be able to identify possible links in the causal relationship between HBV infection and hepatocellular carcinoma.
