Reduction of covalently closed circular DNA with long-term nucleos(t)ide analogue treatment in chronic hepatitis B

postprin

Seven-Year Treatment Outcome of Entecavir in a Real-World Cohort: Effects on Clinical Parameters, HBsAg and HBcrAg Levels

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The hepatitis B core protein associates with HBV covalently closed circular DNA via the C-terminal domain and facilitates HBV transcription

Poster Sessio

Effect of the hepatitis B core protein C-terminal domain mutations on HBV transcription

Poster Presentations: Viral hepatitis: Hepatitis B & D – experimental: no. THU-181BACKGROUND AND AIMS: The hepatitis B core protein (HBc) is a component of the HBV covalently closed circular DNA (cccDNA) minichromosome, the transcription template of HBV. The HBc C-terminal domain (CTD) contains an arginine-rich region, which has been shown to be responsible for nucleic acid binding and efficient HBV RNA encapsidation and reverse transcription. It has been implicated that HBV transcription is regulated by the association of HBc to cccDNA. However, direct evidence demonstrating the effect of HBc on HBV transcription is lacking. We aimed to study the effect of HBc mutations on HBV transcription using a cccDNA-dependent study system …Link_to_subscribed_fulltex

Role of hepatitis B core protein in HBV transcription and recruitment of histone acetyltransferases to cccDNA minichromosome

The hepatitis B core protein (HBc) has been suggested to interact with covalently closed circular DNA (cccDNA) and regulate hepatitis B virus (HBV) transcription. However, direct evidence is lacking. We aimed to identify the specific HBc region(s) responsible for transcription regulation and its interaction with cccDNA. Seventeen mutants with mutations at the four arginine-rich clusters of the HBc carboxyl-terminal domain (CTD) were created. The effect of HBc mutations on the levels of HBV DNA, RNA, and hepatitis B surface antigen (HBsAg) were measured. The association of cccDNA with mutant HBc and histone acetyltransferases (HATs) was assessed by chromatin immunoprecipitation (ChIP). Compared with wild-type HBc, HBc mutants with mutations in clusters III and IV resulted in a significant reduction in HBV RNA levels (all P < 0.05). HBc arginine clusters III and IV mutants also had a significantly lower levels of intracellular HBV DNA (<5% of wild-type; P < 0.001) and HBsAg (<10% of wild-type; P < 0.0001). cccDNA-ChIP assay demonstrated that HBc clusters III and IV mutants had a smaller degree of association with cccDNA (P < 0.001). In the HBc mutants, the association between HATs with cccDNA were reduced. In conclusion, HBc-CTD arginine residues at clusters III and IV play an important role in the regulation of HBV transcription as well as subsequent replication steps, likely through the reduced interaction of HBc with cccDNA and reduced acetylation of cccDNA-bound histones. These findings may provide clues to the identification of novel therapeutic targets against HBV