REVIEW article
Front. Immunol.
Sec. Viral Immunology
This article is part of the Research TopicLiver Diseases – From Pathophysiology to New Treatment OptionsView all 18 articles
Innate Immune Recognition and Evasion Strategies of Hepatitis B Virus: From DNA to RNA and Viral Proteins
Provisionally accepted
- First Affiliated Hospital of Wenzhou Medical University, Wenzhou, China
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Innate immunity constrains the hepatitis B virus (HBV) by sensing pathogen-associated molecular patterns (PAMPs) and inducing type I/III interferons and interferon-stimulated genes. This review synthesizes molecular mechanisms by which HBV nucleic acids and proteins are detected by pattern recognition receptors (PRRs) and how the virus evades such surveillance. At the DNA level, covalently closed circular DNA (cccDNA) persists as a chromatin-like episome with low immunogenicity; cGAS–STING signaling is functionally dampened, whereas nuclear interferon-inducible protein 16(IFI16) and cytoplasmic/nuclear ABCF1 bind cccDNA to repress transcription, and APOBEC3A-mediated deamination requires robust interferon signaling. At the RNA level, TLR3/7/8 and retinoic acid-inducible Gene I(RIG-I) sense circulating HBV RNA and 5′-triphosphate pregenomic RNA, respectively. HBV counteracts RIG-I-like receptor (RLR) pathways through ADAR1 editing, TIAR-dependent translational control, and a metabolic checkpoint involving lactate-MAVS/hexokinase, whereas spliced viral RNAs (svRNAs) have emerged as immunologically relevant species. At the protein level, Hepatitis B Surface Antigen (HBsAg) impairs interferons (IFN) induction by blocking the TAK1– TAB2–NF-κB/IRF axis; Hepatitis B Virus X Protein (HBx) sustains cccDNA transcription via DDB1-directed Smc5/6 degradation and broadly suppresses PRR/IFN signaling, with TRIM25 acting as a host restriction factor. These insights nominate combinatorial strategies—PRR agonists (TLR/STING), MAVS sensitization, metabolic disinhibition, pharmacological disruption of the HBx–DDB1 axis, and reinforcement of IFI16/ABCF1— to achieve functional control of cccDNA and advance curative hepatitis B virus (HBV) therapy.
Keywords: CccDNA, cGAS–STING, HBx, Hepatitis B virus, Immune Evasion, innate immunity, PRRs, RIG-I/MAVS
Received: 07 Nov 2025; Accepted: 10 Feb 2026.
Copyright: © 2026 Chen, Hu, Ye, Chen, Liu, Wu, Chen and Jin. This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) or licensor are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.
* Correspondence: Ciliang Jin
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