Evidence map›Paper›PMID 39570046›Full record

ArticlemBio2024

Augmented epigenetic repression of hepatitis B virus covalently closed circular DNA by interferon-α and small-interfering RNA synergy.

Kongying Hu, Wenjing Zai, Mingzhu Xu, Haiyu Wang, Xinluo Song, Chao Huang, Jiangxia Liu, Juan Chen, Qiang Deng, Zhenghong Yuan and 1 more

Abstract read
PubMed Full text at PMC Publisher
In one paragraph

Article in mBio, 2024. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 6 papers.

0numbers the graph read from it
0cells of the map it votes in
6citing papers in PubMed
–field-weighted citation impact
1 · What the graph read from it

What it found

Each row is one number read from the abstract, on the scale the paper reported it, with its interval. Left of the dashed line favours the treatment, right favours the comparator. Under each row is the sentence it came from. New to these charts? A ten-minute tutorial.

The abstract states no effect estimate the extractor could read, or names no intervention and outcome on the map, so this paper lights no cell and moves no belief. It is still indexed, cited and linked below.

2 · The registry

The trial behind it

Trials whose registry record cites this paper, or whose number appears in the abstract. A trial that started after this paper was published is citing it as background, not reporting it.

Neither the registry nor the abstract names a trial number. If this is a trial report, that itself is worth knowing.

3 · Its place in the literature

Who cites it

6 citing papers in PubMed.

  1. Article
  2. Review
  3. Article
  4. Targeting HBV with RNA interference: Paths to cure.Science translational medicine · 2025
    Review
  5. Review
  6. Article
4 · The record

Corrections and comments

PubMed lists nothing against this paper. Absence here is not a guarantee, only a check that was made.

5 · Who and what money

Authors and funding

11 authors.

Kongying Hu *Key Laboratory of Medical Molecular Virology (MOE/NHC/CAMS), Research Unit of Cure of Chronic Hepatitis B Virus Infection (CAMS), Shanghai Frontiers Science Center of Pathogenic Microbes and Infection, School of Basic Medical Sciences, Shanghai Medical College Fudan University, Shanghai, China.
Wenjing Zai *Key Laboratory of Medical Molecular Virology (MOE/NHC/CAMS), Research Unit of Cure of Chronic Hepatitis B Virus Infection (CAMS), Shanghai Frontiers Science Center of Pathogenic Microbes and Infection, School of Basic Medical Sciences, Shanghai Medical College Fudan University, Shanghai, China.
Mingzhu XuKey Laboratory of Medical Molecular Virology (MOE/NHC/CAMS), Research Unit of Cure of Chronic Hepatitis B Virus Infection (CAMS), Shanghai Frontiers Science Center of Pathogenic Microbes and Infection, School of Basic Medical Sciences, Shanghai Medical College Fudan University, Shanghai, China.
Haiyu WangKey Laboratory of Medical Molecular Virology (MOE/NHC/CAMS), Research Unit of Cure of Chronic Hepatitis B Virus Infection (CAMS), Shanghai Frontiers Science Center of Pathogenic Microbes and Infection, School of Basic Medical Sciences, Shanghai Medical College Fudan University, Shanghai, China.
Xinluo SongKey Laboratory of Medical Molecular Virology (MOE/NHC/CAMS), Research Unit of Cure of Chronic Hepatitis B Virus Infection (CAMS), Shanghai Frontiers Science Center of Pathogenic Microbes and Infection, School of Basic Medical Sciences, Shanghai Medical College Fudan University, Shanghai, China.
Chao HuangKey Laboratory of Medical Molecular Virology (MOE/NHC/CAMS), Research Unit of Cure of Chronic Hepatitis B Virus Infection (CAMS), Shanghai Frontiers Science Center of Pathogenic Microbes and Infection, School of Basic Medical Sciences, Shanghai Medical College Fudan University, Shanghai, China.
Jiangxia LiuKey Laboratory of Medical Molecular Virology (MOE/NHC/CAMS), Research Unit of Cure of Chronic Hepatitis B Virus Infection (CAMS), Shanghai Frontiers Science Center of Pathogenic Microbes and Infection, School of Basic Medical Sciences, Shanghai Medical College Fudan University, Shanghai, China.
Juan ChenKey Laboratory of Molecular Biology of Infectious Diseases (MOE), Chongqing Medical University, Chongqing, China.
Qiang DengKey Laboratory of Medical Molecular Virology (MOE/NHC/CAMS), Research Unit of Cure of Chronic Hepatitis B Virus Infection (CAMS), Shanghai Frontiers Science Center of Pathogenic Microbes and Infection, School of Basic Medical Sciences, Shanghai Medical College Fudan University, Shanghai, China.
Zhenghong YuanKey Laboratory of Medical Molecular Virology (MOE/NHC/CAMS), Research Unit of Cure of Chronic Hepatitis B Virus Infection (CAMS), Shanghai Frontiers Science Center of Pathogenic Microbes and Infection, School of Basic Medical Sciences, Shanghai Medical College Fudan University, Shanghai, China.ORCID 0000-0003-0268-4891
Jieliang ChenKey Laboratory of Medical Molecular Virology (MOE/NHC/CAMS), Research Unit of Cure of Chronic Hepatitis B Virus Infection (CAMS), Shanghai Frontiers Science Center of Pathogenic Microbes and Infection, School of Basic Medical Sciences, Shanghai Medical College Fudan University, Shanghai, China.ORCID 0000-0002-9647-0239

Funding

No grant is acknowledged in the PubMed record.

6 · The paper itself

Abstract

The persistence of hepatitis B virus (HBV) covalently closed circular DNA (cccDNA) is a key obstacle for HBV cure. This study aims to comprehensively assess the effect of interferon (IFN) and small-interfering RNA (siRNA) combination on the cccDNA minichromosome. Utilizing both cell and mouse cccDNA models, we compared the inhibitory effects of IFNα, siRNA, and their combination on cccDNA activity and assessed its epigenetic state. IFNα2 treatment alone reduced HBV RNAs, HBeAg, and HBsAg levels by approximately 50%, accompanied by a low-level reconstitution of SMC5/6-a chromatin modulator that restricts cccDNA transcription. HBx-targeting siRNA (siHBx) achieved significant suppression of viral antigens and reconstitution of SMC5/6, but this effect could be reversed by the deacetylase inhibitor Belinostat. The combination of IFN with siHBx resulted in over 95% suppression of virological markers, reduction in epigenetic activation modifications (H3Ac and H4Ac) on cccDNA, and further reduced cccDNA accessibility, with the effect not reversible by Belinostat. In an extracellular humanized IFNAR C57BL/6 mouse model harboring recombinant cccDNA, the effect of combination of clinically used pegylated IFNα2 and GalNac-siHBx was further clarified, indicating a higher and more durable suppression of cccDNA activity compared to either therapy alone. In conclusion, the combination of IFNα and siRNA achieves a more potent and durable epigenetic inhibition of cccDNA activity in cell and mouse models, compared to monotherapy. These findings deepen the understanding of cccDNA modulation and strengthen the scientific basis for the potential of combination therapy. IMPORTANCE: Since there are currently no approved drugs targeting and silencing covalently closed circular DNA (cccDNA), achieving a "functional cure" remains difficult. This study aims to comprehensively compare the effects of IFNα, small-interfering RNA targeting hepatitis B virus (HBV), and their combination on the activity, accessibility, and epigenetic modifications of cccDNA minichromosomes in cell models. A more durable and stable inhibition of HBV RNAs and antigens expression by IFNα and HBx-targeting siRNA (siHBx) synergy was observed, associated with augmented epigenetic repression of the cccDNA minichromosome. Besides, in an extracellular humanized IFNAR mouse model harboring recombinant cccDNA with an intact response to human IFNα, the synergistic effect of clinically used pegylated IFNα2 and in-house-developed GalNac-siHBx was further clarified.

Indexed as

DNA, CircularDNA, ViralEpigenesis, GeneticHepatitis B virusInterferon-alphaRNA, Small InterferingAnimalsAntiviral AgentsHepatitis BHumansMiceMice, Inbred C57BLVirus ReplicationAntiviral AgentsDNA, CircularDNA, ViralInterferon-alphaRNA, Small InterferingcccDNAcombination therapyepigenetic modulationHBVIFNsiRNA

Identifiers

PMID39570046
PMCPMC11633095

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Registered trials

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Read under generation 80e0d062 · epoch 390. Bibliography from PubMed, PubMed Central and OpenAlex; grants from NIH RePORTER; trial links from ClinicalTrials.gov; estimates, votes and beliefs from the OpenQuestion graph.