Multiple liver-specific factors bind to the hepatitis B virus core/pregenomic promoter: trans-activation and repression by CCAAT/enhancer binding protein.

The human hepatitis B virus (HBV) is a hepatotropic virus that replicates through an RNA intermediate referred to as the pregenome. The promoter that directs the synthesis of the pregenome and several other transcripts with heterogeneous 5' ends is of particular interest because of its role in regulating key functions during the viral life cycle. We have examined the liver-specific characteristics of this promoter by DNA-protein interactions and by demonstrating the in vivo function of the promoter using the luciferase reporter gene expression system. The DNA-protein interactions in this region appear to be almost entirely liver-specific. Among these, a liver-specific nuclear factor, CCAAT/enhancer binding protein, binds to at least five sites on this promoter. Transient cotransfection experiments using CCAAT/enhancer binding protein expression vectors and the core promoter in the context of either the native hepatitis B virus genome or the luciferase reporter gene demonstrate that CCAAT/enhancer binding protein at low concentration modestly activates expression from the core promoter but represses at high concentration.