Augmented epigenetic repression of hepatitis B virus covalently closed circular DNA by interferon-α and small-interfering RNA synergy
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.
Authors
- Chao Huang (ORCID: https://orcid.org/0000-0002-6210-0715)
- Qiang Deng (ORCID: https://orcid.org/0000-0002-3381-3417)
- Jieliang Chen (ORCID: https://orcid.org/0000-0002-9647-0239)
- H L Wang (ORCID: https://orcid.org/0009-0005-8690-2818)
- Kongying Hu
- Xinluo Song
- Jiangxia Liu
- Zhenghong Yuan (ORCID: https://orcid.org/0000-0003-0268-4891)
- Juan Chen (ORCID: https://orcid.org/0000-0003-4324-7460)
- Wenjing Zai (ORCID: https://orcid.org/0000-0003-2550-331X)
- Mingzhu Xu
Institutions
- Shanghai Medical College of Fudan University (CN)
- Fudan University (CN)
- Chongqing Medical University (CN)
Publication Details
- Journal
- mBio
- Published
- 2024-11-21
- DOI
- https://doi.org/10.1128/mbio.02415-24
- Citations
- 8
- Primary Topic
- Hepatitis B Virus Studies
- Type
- article
- Field-Weighted Citation Impact
- 3.09
Funders
- Fudan University
- Ministry of Education, India
- Chinese Academy of Medical Sciences
- Shanghai Medical College, Fudan University