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Hepatitis B virus (HBV) mutants unable to synthesize HBV e antigen have been described in association with fulminant hepatitis. We have cloned and sequenced the entire viral genome of an HBV strain associated with an epidemic of fulminant hepatitis. This strain contained, in addition to two G-to-A mutations in the precore region (nucleotides 1898 and 1901), numerous other mutations in conserved nucleotide positions resulting in significant amino acid substitutions in HBV gene products. We introduced either or both of the two G-to-A mutations into wild-type HBV by oligonucleotide-directed mutagenesis and generated replication-competent constructs of these mutants as well as the fulminant strain. Viral antigen synthesis, transcription, and replication were analyzed after transfection into human hepatoma cells. All viral constructs produced and secreted similar levels of envelope proteins (HBV surface antigen). Analysis of cellular lysate for core-specific immunoreactivity demonstrated a much higher level of core-associated antigens in cells transfected with the fulminant strain. While cells transfected with mutant and wild-type HBV DNAs synthesized similar levels of viral RNAs, the fulminant strain directed the synthesis of a much higher level of core-associated replicative intermediates (as well as virion particles) than the wild type and mutants with either or both of the precore mutations. Increase in the encapsidation of pregenomic RNA into core particles likely the basis for the enhanced replication associated with the fulminant strain. Our study suggests that an HBV mutant with enhanced viral replication may be important in the pathogenesis of fulminant hepatic failure, and mutations other than the precore mutations may be responsible for this variant behavior.