Innate immune recognition and evasion strategies of hepatitis B virus: from DNA to RNA and viral proteins

TL;DR

This paper reviews how the hepatitis B virus evades the body's innate immune system and suggests new therapeutic strategies to combat it.

Contribution

The paper provides a comprehensive synthesis of HBV immune evasion mechanisms and proposes novel combinatorial therapeutic approaches.

Findings

HBV DNA and RNA are sensed by PRRs, but the virus employs strategies to evade detection.

HBV proteins like HBsAg and HBx interfere with interferon signaling pathways.

New therapeutic strategies include PRR agonists and disruption of the HBx–DDB1 axis.

Abstract

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.

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