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The A1762T/G1764A mutations enhance HBV replication by alternating viral transcriptome.
Danli Yang1, Jun Zou1,2, Guiwen Guan1
1Department of Microbiology and Infectious Disease Center, School of Basic Medical Sciences, Peking University, Beijing, China.
Journal of Medical Virology
|September 29, 2023
Summary
Common mutations in hepatitis B virus basal core promoter enhance viral replication by upregulating pregenomic RNA and creating a HNF1α binding site. These findings offer insights into chronic HBV infection management and potential therapeutic targets.
Area of Science:
- Virology
- Hepatology
- Molecular Biology
Background:
- The A1762T/G1764A mutations are prevalent in the hepatitis B virus (HBV) basal core promoter (BCP).
- These mutations are linked to chronic HBV (CHB) infection progression, but their precise impact on HBV replication is debated.
Purpose of the Study:
- To systematically investigate the effects of A1762T/G1764A mutations on HBV replication.
- To elucidate the underlying molecular mechanisms driving these effects.
Main Methods:
- Construction of a recombinant plasmid carrying the A1762T/G1764A mutant.
- Assessment of HBV replication using quantitative assays (HBV DNA/RNA levels, Southern/Northern blots).
- Analysis of viral transcription (5'-RACE, transcriptome sequencing) and protein expression.
- In vitro infection models (HepG2-NTCP cells) and in vivo experiments (mice hydrodynamic injection).
- Chromatin immunoprecipitation followed by quantitative PCR (ChIP-qPCR) to identify transcription factor binding sites.
Main Results:
- A1762T/G1764A mutant HBV exhibited enhanced replication with increased HBV DNA and RNA levels.
- Mutations led to higher intracellular levels of relaxed circular DNA, single-stranded DNA, and 3.5 kb RNA.
- Intracellular core protein expression increased, while HBeAg and HBsAg production decreased.
- Transcriptome analysis revealed upregulation of pregenomic RNA (pgRNA) and downregulation of preC RNA.
- A functional HNF1α binding site was created in the BCP region by the mutations, enhancing HBV replication.
Conclusions:
- The A1762T/G1764A mutations significantly promote HBV replication through mechanisms involving altered pgRNA transcription and HNF1α binding.
- These mutations serve as important indicators for managing CHB patients.
- Hepatocyte Nuclear Factor 1-alpha (HNF1α) presents a potential therapeutic target for treating HBV infection.
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