EFFECTS OF A NATURALLY-OCCURRING MUTATION IN THE HEPATITIS-B VIRUS BASAL CORE PROMOTER ON PRECORE GENE-EXPRESSION AND VIRAL REPLICATION

The basal core promoter (BCP) of hepatitis B virus (HBV) controls the transcription of both the precore RNA and the core RNA, The precore RN A codes for the secreted e antigen, while the core RNA codes for the m ajor core protein and the DNA polymerase and also is the pregenomic RN A. The double mutation of nucleotides 1762 and 1764 in the BCP from A and G to T and A, respectively, is frequently observed in HBV sequence s isolated from chronic patients, Several papers have reported conflic ting results regarding whether this double mutation is important for e antigen expression, In order to address this issue, we have introduce d this double mutation into the HBV genome and studied its effects on HBV gene expression and replication. Our results indicate that the mut ated BCP can no longer bind a liver-enriched transcription factor(s) a nd that the transcription of only precore RNA and, consequently, the e xpression of e antigen were reduced. The reduction of precore gene exp ression was accompanied by an increase in progeny virus production. Th is increase was found to occur at or immediately prior to the encapsid ation of the pregenomic RNA. Thus, the results of our in vitro study r esolve the discrepancy of previous clinical observations and indicate that this double mutation suppresses but does not abolish the e antige n phenotype, The implications of these findings in the pathogenesis of HBV are discussed.