State Key Laboratory of Medical Molecular Biology, Institute of Basic Medical Sciences, Chinese Academy of Medical Sciences, School of Basic Medicine, Peking Union Medical College, Beijing 100005, P.R. China.
Department of Interventional Radiology, the Affiliated Hospital of Qingdao University, Shandong 266003, P.R. China.
Mol Ther. 2021 Mar 3;29(3):1335-1348. doi: 10.1016/j.ymthe.2020.11.031. Epub 2020 Dec 3.
The partial response of chronic hepatitis B virus (CHB) patients to interferon-α (IFN-α) therapy remains elusive, which requires a better understanding of the involved molecular mechanism. In our study, bioinformatics analysis was applied to relate IFN-α regulated candidate genes and RNA editing sites by RNA sequencing. Mitochondrial antiviral signaling protein (MAVS) antiviral effect was confirmed in HepG2.2.15 cells and in two mouse models. The associations between polymorphisms in MAVS gene and response to IFN-α therapy were confirmed in CHB patients. We found that IFN-α downregulates MAVS via RNA editing that was mediated by adenosine deaminase acting on RNA (ADAR1). ADAR1 inhibited MAVS expression via a human antigen R (HuR)-mediated post-transcriptional regulation. MAVS exerted an antiviral activity and reduced the level of hepatitis B virus (HBV) markers in vitro and in vivo. IFN-α antiviral effects were significantly enhanced by MAVS co-transfection. Hepatitis B core protein (HBc) interacted with SP1 to inhibit the promoter activity of MAVS that regulates its expression. CHB patients with a rs3746662A allele had higher MAVS expression and thus were more responsive to IFN-α treatment. In this work, we demonstrated that the decrease of MAVS expression is mediated by the IFN-α-ADAR1 axis. This study also highlighted the potential for the clinical application of MAVS in combination with IFN-α for the treatment of HBV infection.
慢性乙型肝炎病毒（CHB）患者对干扰素-α（IFN-α）治疗的部分反应仍然难以捉摸，这需要更好地了解相关的分子机制。在我们的研究中，应用生物信息学分析方法来关联 IFN-α 调节的候选基因和 RNA 测序中的 RNA 编辑位点。在 HepG2.2.15 细胞和两种小鼠模型中证实了抗病毒信号蛋白（MAVS）的抗病毒作用。在 CHB 患者中证实了 MAVS 基因多态性与 IFN-α 治疗反应之间的关联。我们发现 IFN-α 通过 RNA 编辑下调 MAVS，该编辑由 RNA 作用的腺苷脱氨酶（ADAR1）介导。ADAR1 通过 HuR 介导的转录后调控抑制 MAVS 表达。MAVS 在体外和体内发挥抗病毒活性并降低乙型肝炎病毒（HBV）标志物的水平。MAVS 共转染显著增强了 IFN-α 的抗病毒作用。乙型肝炎核心蛋白（HBc）与 SP1 相互作用，抑制 MAVS 启动子活性，从而调节其表达。具有 rs3746662A 等位基因的 CHB 患者具有更高的 MAVS 表达水平，因此对 IFN-α 治疗更敏感。在这项工作中，我们证明了 MAVS 表达的降低是由 IFN-α-ADAR1 轴介导的。本研究还强调了 MAVS 与 IFN-α 联合用于治疗 HBV 感染的临床应用潜力。
