Hepatitis B virus transcription and replication

Hepatitis B virus (HBV) replicates by the reverse transcription of the 3.5-kb viral pregenomic RNA. Therefore, the regulation of the transcription of the pregenomic RNA is a critical step in the viral life cycle. Various ubiquitous and liver-enriched transcription factors have been shown to modulate the level of RNA synthesis from the core promoter. The nuclear hormone receptors HNF4 and RXRalpha plus PPARalpha appear to have a critical role in governing pregenomic RNA synthesis from the core promoter in cell culture and probably represent a major determinant governing the hepatotropism of this virus. The level of 3.5-kb HBV RNA synthesis is approximately proportional to the level of viral replication in cell culture; however, this is not the case in the liver of HBV transgenic mice. Directly modulating the levels or activities of specific transcription factors known to regulate HBV transcription in cell culture can increase viral replication in HBV transgenic mice without greatly changing the levels of HBV transcripts. Various immune stimuli that alter transcription factor activities involved in regulating viral RNA synthesis can negatively affect viral replication without affecting HBV transcription. These observations suggest that in vivo very subtle changes in HBV transcription may contribute to large alterations, either negative or positive, in viral replication. Investigation of transcription factor-null HBV transgenic mice under various physiological conditions will be required to establish the putative role of specific transcription factors in regulating viral replication in vivo.