In vivo suppression of precore mRNA synthesis is associated with mutations in the hepatitis B virus core promoter.

We have examined the in vivo effect of hepatitis B virus (HBV) core promoter mutations on the expression of precore mRNA and pregenomic RNA transcripts in the liver of 24 patients with chronic HBV infection, applying a novel transcript-specific RT-PCR assay. The double A1762T/G1764A mutation in the basic core promoter was detected in 11 cases. This mutation was in all cases associated with absence or low levels of precore mRNA transcripts without significantly affecting the levels of total core promoter-directed transcription in the liver of infected patients. Precore mRNA synthesis was suppressed by the A1762T/G1764A mutation regardless of the presence of the precore stop codon mutation G1896A, suggesting that in addition to downregulating an immunomodulatory protein this double basic core promoter mutation may also confer a replication advantage to the virus. Additional mutations detected in the core promoter may also contribute to the observed changes in precore mRNA levels. Our in vivo study shows therefore that the double A1762T/G1764A mutation is associated with the specific suppression of precore mRNA synthesis directed by the HBV core promoter.