Lee Sooyoung, Goyal Ashish, Perelson Alan S, Ishida Yuji, Saito Takeshi, Gale Michael
Center for Innate Immunity and Immune Disease, Department of Immunology, University of Washington, Seattle, WA 98109, USA.
Theoretical Biology and Biophysics, Los Alamos National Laboratory, Los Alamos, NM, USA.
iScience. 2021 Jan 4;24(1):101969. doi: 10.1016/j.isci.2020.101969. eCollection 2021 Jan 22.
Hepatitis B virus (HBV) mediates persistent infection, chronic hepatitis, and liver disease. HBV covalently closed circular (ccc)DNA is central to viral persistence such that its elimination is considered the cornerstone for HBV cure. Inefficient detection by pathogen recognition receptors (PRRs) in the infected hepatocyte facilitates HBV persistence via avoidance of innate immune activation and interferon regulatory factor (IRF)3 induction of antiviral gene expression. We evaluated a small molecule compound, F7, and 5'-triphosphate-poly-U/UC pathogen-associated-molecular-pattern (PAMP) RNA agonists of RIG-I, a PRR that signals innate immunity, for ability to suppress cccDNA. F7 and poly-U/UC PAMP treatment of HBV-infected cells induced RIG-I signaling of IRF3 activation to induce antiviral genes for suppression of cccDNA formation and accelerated decay of established cccDNA, and were additive to the actions of entecavir. Our study shows that activation of the RIG-I pathway and IRF3 to induce innate immune actions offers therapeutic benefit toward elimination of cccDNA.
乙型肝炎病毒（HBV）介导持续性感染、慢性肝炎和肝病。HBV共价闭合环状（ccc）DNA是病毒持续存在的核心，因此其清除被认为是治愈HBV的基石。感染的肝细胞中病原体识别受体（PRR）的检测效率低下，通过避免先天免疫激活和干扰素调节因子（IRF）3诱导抗病毒基因表达，促进了HBV的持续存在。我们评估了一种小分子化合物F7，以及RIG-I（一种发出先天免疫信号的PRR）的5'-三磷酸-聚-U/UC病原体相关分子模式（PAMP）RNA激动剂抑制cccDNA的能力。用F7和聚-U/UC PAMP处理HBV感染的细胞，可诱导RIG-I信号激活IRF3，从而诱导抗病毒基因，抑制cccDNA形成并加速已建立的cccDNA的降解，并且与恩替卡韦的作用相加。我们的研究表明，激活RIG-I途径和IRF3以诱导先天免疫作用，对消除cccDNA具有治疗益处。
