Hepatitis B virus X‐gene product: A promiscuous transcriptional activator

The disease state induced by infection with hepatitis B virus (HBV) is manifest in varying ways characterised by the extent of liver inflammation and damage and viral persistence. In a small percentage of cases, primary infection leads to fulminant hepatitis resulting in severe liver dysfunction with very high mortality. Primary infection is most often resolved by complete clearance of the virus and development of immune memory to counter reinfection, but 5‐10% of infected adults develop chronic infection characterised by the persistence of viral antigens in the serum and accompanied by varying degrees of hepatic injury. This disease state may continue after integration of HBV DNA into the hepatocyte genome from which transcription of viral antigen genes may continue in the absence of virion production. Chronically infected patients are predisposed to developing hepatocellular carcinoma (HCC) [Szmuness, 1978] with more than 100‐fold greater probability than non‐infected individuals [Beasley, et al., 1981]. Hepatitis B constitutes a major worldwide health problem with the number of chronically infected people currently estimated in excess of 250 million. HBV is the prototype member of the family of hepadnaviridae, which includes hepatitis viruses isolated from the woodchuck (WHV) [Summers et al., 1978], ground squirrel (GSHV) [Marion et al., 1980], Pekin duck (DHBV) [Mason et al., 1980], and grey heron (HHV) [Sprengel et al., 1988]. This taxonomy is derived from the relative hepatropism of virus family members, their common virion morphology, genome size, structure and organisation, and common mechanism of genome replication, which proceeds through reverse transcription of an RNA intermediate [Summers and Mason, 1982] in a manner analogous to that of retroviruses. All the viruses exhibit a strict host specificity, the human virus replicating only in man and a small number of higher apes. HBV has a partially double stranded, open‐circular genome of 3.2 kilobases (kb) which contains four open reading frames (ORFs) including the S ‐gene encoding the surface antigen and the C ‐gene encoding the core antigen (Fig. 1 ). A large ORF encompassing most of the viral genome encodes the viral polymerase while the fourth ORF encodes a protein of 154 amino acid residues which has been termed the X antigen (HBxAg) because the function of this product in the viral lifecycle is still under intensive investigation.