Hepatitis B virus (HBV) infection can cause a wide spectrum of sequelae, ranging from asymptomatic chronic infection to chronic active hepatitis. Three hundred million people around the world are chronically infected with HBV (38, 39). Clinically, it is estimated that 5 to 10% of HBV-infected adults will develop chronic hepatitis (CH) and will thus be at a higher (Ͼ100 times) risk of developing hepatocellular carcinoma (HCC) (1,12,41). Several viral and host factors have been suggested to be involved in the chronicity and diversity of HBV-associated disease (25, 43). The association, at the molecular level, between HBV infection and HBV-related diseases remains unclear.The small, 3.2-kb DNA genome of HBV contains four known open reading frames, called S, C, P, and X. The hepatitis B virus X (HBx) gene is the smallest, with a length of 465 nucleotides (10). HBx protein is 154 amino acids long, with a molecular weight (MW) of 17,000, and is conserved among all mammalian hepadnaviruses, but the deduced amino acid sequence of the HBx gene product does not correspond to any known viral proteins (26). Although the HBx protein has been shown to stimulate cell cycle progression of quiescent cells (18), it is mainly a pleiotropic transactivator, due to its ability to stimulate not only the HBV promoter and enhancer (28, 33) but also a wide range of other viral promoters (33,35,40). The necessity for HBx gene expression during the viral life cycle, in vitro and in vivo, has been suggested (3, 44). The HBx protein acts either through interaction with other cellular transcription factors or via a signal transduction pathway controlled by protein kinase C (15, 30, 31). As a consequence of its activity, the HBx protein appears capable of inducing transformation (32) and liver tumors in a selected strain of mice that express the HBx protein from a transgene (16,17).During the natural course of HBV infection, the HBx gene expresses a polypeptide, HBx, that is implicated in HBV-mediated HCC (4, 16). When liver tissue samples from HCC and CH patients were reacted with an anti-HBx antibody and evaluated by immunohistochemistry, reactive antigen was detected in 80% of HCC liver samples and 30% of CH liver samples (4). In another study, the sera of patients with acute hepatitis, CH, and cirrhosis were tested for HBx protein and anti-HBx antibodies by an enzyme-linked immunosorbent assay (ELISA) using a monoclonal antibody and recombinant HBx protein.The results indicated that 23% of patients' sera were HBx positive and 14% of patients' sera were anti-HBx positive (20). In another approach, using HBx oligopeptides as antigens to detect antibodies in the sera of HCC patients, 73% of HCC sera tested positive for anti-HBx antibodies (27). With similar approaches, data showed that 74% of sera from patients with cirrhosis and 54% of sera from patients with HCC were positive for anti-HBx antibodies and HBV surface antigen (HBs) (36). Therefore, the expression of HBx protein in infected patients did not correlate well with the occurrence of...

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