Beijing Key Laboratory of Antimicrobial Agents, Institute of Medicinal Biotechnology, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China; NHC Key Laboratory of Biotechnology of Antibiotics, Institute of Medicinal Biotechnology, Chinese Academy of Medical Science, Beijing, 100050, China.
CAMS Key Laboratory of Antiviral Drug Research, Institute of Medicinal Biotechnology, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China.
Antiviral Res. 2019 May;165:23-33. doi: 10.1016/j.antiviral.2019.03.005. Epub 2019 Mar 9.
Enterovirus 71 (EV71), a single-stranded positive-sense RNA virus, is the causative agent of hand, foot, and mouth disease (HFMD), for which no effective antiviral therapy is currently available. Apolipoprotein B messenger RNA-editing enzyme catalytic polypeptide-like 3G (APOBEC3G or A3G) is a cytidine deaminase that inhibits the replication of several viruses, such as human immunodeficiency virus-1, hepatitis B virus and hepatitis C virus. In our efforts toward understanding the antiviral spectrum and mechanism of A3G, we found that ectopic expression of A3G inhibited EV71 replication, whereas knockdown of endogenous A3G expression promoted EV71 replication. Moreover, inhibition of EV71 replication by IMB-Z, a N-phenylbenzamide derivative, is associated with increased levels of intracellular A3G, but reducing the level of A3G by RNA interference diminished the antiviral activity of IMB-Z. Mechanistically, we obtained evidence suggesting that the cytidine deaminase activity is not required for A3G inhibition of EV71 replication. Instead, we demonstrated that A3G can interact with viral 3D RNA-dependent RNA polymerase (RdRp) and viral RNA and be packaged into progeny virions to reduce its infectivity. Taken together, our results indicate that A3G is a cellular restriction factor of EV71 and mediator of the antiviral activity of IMB-Z. Pharmacological induction and/or stabilization of A3G is a potential therapeutic approach to treat diseases caused by EV71 infection, such as HFMD.
肠道病毒 71 型（EV71）是一种单链正链 RNA 病毒，是手足口病（HFMD）的病原体，目前尚无有效的抗病毒治疗方法。载脂蛋白 B mRNA 编辑酶催化多肽样 3G（APOBEC3G 或 A3G）是一种胞嘧啶脱氨酶，可抑制几种病毒的复制，如人类免疫缺陷病毒-1、乙型肝炎病毒和丙型肝炎病毒。在我们努力了解 A3G 的抗病毒谱和机制的过程中，我们发现 A3G 的异位表达抑制了 EV71 的复制，而内源性 A3G 表达的下调促进了 EV71 的复制。此外，IMB-Z（一种 N- 苯甲酰胺衍生物）抑制 EV71 复制与细胞内 A3G 水平升高有关，但通过 RNA 干扰降低 A3G 水平会减弱 IMB-Z 的抗病毒活性。从机制上讲，我们获得的证据表明，胞嘧啶脱氨酶活性不是 A3G 抑制 EV71 复制所必需的。相反，我们证明 A3G 可以与病毒 3D RNA 依赖性 RNA 聚合酶（RdRp）和病毒 RNA 相互作用，并被包装到子代病毒中，从而降低其感染力。总之，我们的结果表明，A3G 是 EV71 的一种细胞限制因子，也是 IMB-Z 抗病毒活性的介导物。药理学诱导和/或稳定 A3G 是治疗由 EV71 感染引起的疾病（如 HFMD）的潜在治疗方法。
