HBV is considered as a “stealth” virus that does not invoke interferon (IFN) responses; however, the mechanisms by which HBV bypasses innate immune recognition are poorly understood. In this study, we identified adenosine deaminases acting on RNA 1 (ADAR1), which is a key factor in HBV evasion from IFN responses in hepatocytes. Mechanically, ADAR1 interacted with HBV RNAs and deaminated adenosine (A) to generate inosine (I), which disrupted host immune recognition and thus promoted HBV replication. Loss of ADAR1 or its deficient deaminase activity promoted IFN responses and inhibited HBV replication in hepatocytes, and blocking the IFN signaling pathways released the inhibition of HBV replication caused by ADAR1 deficiency. Notably, the HBV X protein (HBx) transcriptionally promoted ADAR1 expression to increase the threshold required to trigger intrinsic immune activation, which in turn enhanced HBV escape from immune recognition, leading to persistent infection. Supplementation with 8-azaadenosine, an ADAR1 inhibitor, efficiently enhanced liver immune activation to promote HBV clearance in vivo and in vitro. Taken together, our results delineate a molecular mechanism by which HBx promotes ADAR1-derived HBV immune escape and suggest a targeted therapeutic intervention for HBV infection.

乙型肝炎病毒被认为是一种“隐形”病毒，不会引起干扰素 (IFN) 反应；然而，人们对乙型肝炎病毒绕过先天免疫识别的机制知之甚少。在这项研究中，我们发现了作用于 RNA 1 (ADAR1) 的腺苷脱氨酶，这是 HBV 逃避肝细胞中 IFN 反应的关键因素。从机械角度来看，ADAR1 与 HBV RNA 和脱氨基腺苷 (A) 相互作用，生成肌苷 (I)，从而破坏宿主免疫识别，从而促进 HBV 复制。 ADAR1的缺失或其脱氨酶活性的缺陷促进了IFN反应并抑制了肝细胞中的HBV复制，而阻断IFN信号通路则解除了ADAR1缺陷引起的HBV复制的抑制。值得注意的是，HBV X 蛋白 (HBx) 转录促进 ADAR1 表达，增加触发内在免疫激活所需的阈值，进而增强 HBV 逃避免疫识别的能力，导致持续感染。补充 ADAR1 抑制剂 8-氮杂腺苷可有效增强肝脏免疫激活，从而促进体内和体外的 HBV 清除。总而言之，我们的结果描绘了 HBx 促进 ADAR1 衍生的 HBV 免疫逃逸的分子机制，并提出了针对 HBV 感染的靶向治疗干预措施。