FUNCTIONAL-ANALYSIS OF HBV GENOMES FROM PATIENTS WITH FULMINANT-HEPATITIS

Two previous case reports suggest that hepatitis B virus (HBV) core pr omoter variants with a high replication competence contribute to the p athogenesis of fulminant hepatitis B (FHB). We recently found in HBV g enomes from patients with FHB an accumulation of mutations within the core promoter region. Therefore, the aim of this study was to investig ate the phenotype of these HBV variants. Replication competence and ex pression of hepatitis B surface antigen (HBsAg) and hepatitis B e anti gen (HBeAg) of viral genomes from seven patients with FHB and one pati ent with fulminant recurrent hepatitis after liver transplantation wer e analyzed by transfection experiments in human hepatoma cells. Compar ed with wild-type virus, the HBV variants from the seven patients with FHB produced similar or slightly lower levels of intracellular replic ative intermediates and extracellular viral particles. In contrast, th e HBV genomes from the patient with fulminant recurrent hepatitis synt hesized and secreted significantly more HBV DNA. All genomes tested ex pressed similar or even higher levels of HBeAg compared with wild-type virus, except for those from four patients with a precore stop codon mutation in the respective dominant viral populations. The level of HB sAg produced by all variant genomes was similar or reduced compared wi th wild-type virus. These data indicate that in some cases HBV variant s with enhanced replication competence and/or a defect in HBeAg expres sion may contribute to the development of FHB. However, neither phenot ype is an essential prerequisite; thus, an additional role of other vi ral or host factors in the pathogenesis of FI-IB is suggested.