Hepatitis B virus evades immune recognition via RNA adenosine deaminase ADAR1-mediated viral RNA editing in hepatocytes
Hepatitis B virus evades immune recognition via RNA adenosine deaminase ADAR1-mediated viral RNA editing in hepatocytes
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乙型肝炎病毒通过肝细胞中RNA腺苷脱氨酶ADAR1介导的病毒RNA编辑逃避免疫识别
DOI：
10.1038/s41423-021-00729-1
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发表时间：
2021-07-12
影响因子：
24.1
通讯作者：
Ma, Chunhong
中科院分区：
文献类型：
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作者：
Wang, Liyuan;Sun, Yang;Ma, Chunhong
HBV被认为是一种“隐形”病毒，不引起干扰素（IFN）反应;然而，HBV绕过先天免疫识别的机制知之甚少。在这项研究中，我们确定了腺苷脱氨酶作用于RNA 1（ADAR 1），这是一个关键因素，HBV逃避干扰素反应在肝细胞。ADAR 1与HBV RNA和脱氨基腺苷（A）相互作用产生肌苷（I），破坏宿主免疫识别，从而促进HBV复制。ADAR 1的缺失或其脱氨酶活性的缺陷可促进IFN应答并抑制HBV在肝细胞中的复制，阻断IFN信号通路可解除ADAR 1缺陷引起的HBV复制抑制。值得注意的是，HBV X蛋白（HBx）转录促进ADAR 1表达，以增加触发内在免疫激活所需的阈值，这反过来又增强了HBV逃避免疫识别，导致持续感染。补充ADAR 1抑制剂8-azaadenosine可有效增强肝脏免疫激活，促进体内和体外HBV清除。综上所述，我们的研究结果描绘了HBx促进ADAR 1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。
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.