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Epigenetic regulation and its therapeutic potential in hepatitis B virus covalently closed circular DNA
Jihua Ren1, Shengtao Cheng1, Fang Ren2
1The Key Laboratory of Molecular Biology of Infectious Diseases Designated by the Chinese Ministry of Education, Chongqing Medical University, Chongqing 400000, China.
Insights
Hepatitis B virus (HBV) infection persists due to viral DNA (cccDNA). Understanding cccDNA transcription regulation is key to developing a cure for chronic hepatitis B, offering hope for complete HBV resolution.
Area of Science:
- Hepatology
- Virology
- Molecular Biology
Background:
- Hepatitis B virus (HBV) infection causes significant liver disease, including cancer.
- Current therapies suppress HBV replication but rarely achieve complete viral clearance.
- Persistent covalently closed circular DNA (cccDNA) is the primary barrier to HBV cure.
Purpose of the Study:
- To review the biology of HBV cccDNA.
- To summarize mechanisms regulating cccDNA transcription.
- To discuss novel therapeutic strategies targeting cccDNA for HBV eradication.
Main Methods:
- Literature review of HBV cccDNA biology and regulation.
- Analysis of studies on chromatin modifiers, viral proteins, and noncoding RNAs affecting cccDNA.
- Synthesis of current knowledge on anti-HBV approaches aimed at cccDNA elimination.
Main Results:
- HBV cccDNA forms stable nuclear minichromosomes.
- Chromatin-modifying enzymes, viral proteins, and noncoding RNAs critically regulate cccDNA transcription.
- Understanding these regulatory mechanisms is crucial for developing curative HBV therapies.
Conclusions:
- Targeting cccDNA transcription represents a promising strategy for a functional cure of chronic hepatitis B.
- Further research into cccDNA regulatory networks will accelerate the development of novel anti-HBV treatments.
- Eliminating cccDNA is essential for achieving complete resolution of HBV infection.
Abstract:
Human hepatitis B virus (HBV) infection is the major cause of acute and chronic hepatitis B, liver cirrhosis, and hepatocellular carcinoma. Although the application of prophylactic vaccination programs has successfully prevented the trend of increasing HBV infection prevalence, the number of HBV-infected people remains very high. Approved therapeutic management efficiently suppresses viral replication; however, HBV infection is rarely completely resolved. The major reason for therapeutic failure is the persistence of covalently closed circular DNA (cccDNA), which forms viral minichromosomes by combining with histone and nonhistone proteins in the nucleus. Increasing evidence indicates that chromatin-modifying enzymes, viral proteins, and noncoding RNAs are essential for modulating the function of cccDNA. Therefore, a deeper understanding of the regulatory mechanism underlying cccDNA transcription will contribute to the development of a cure for chronic hepatitis B. This review summarizes the current knowledge of cccDNA biology, the regulatory mechanisms underlying cccDNA transcription, and novel anti-HBV approaches for eliminating cccDNA transcription.
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