AIDS Research Institute-IrsiCaixa and Health Research Institute Germans Trias i Pujol (IGTP), Hospital Germans Trias i Pujol, Universitat Autònoma de Barcelona, Badalona, Spain.
Genomes for Life-GCAT Lab Group - Program of Predictive and Personalized Medicine of Cancer (PMPPC), Health Research Institute Germans Trias i Pujol (IGTP), Badalona, Spain.
Antiviral Res. 2018 Aug;156:116-127. doi: 10.1016/j.antiviral.2018.05.012. Epub 2018 Jun 12.
The hepatitis C virus (HCV) is a globally prevalent infectious pathogen. As many as 80% of people infected with HCV do not control the virus and develop a chronic infection. Response to interferon (IFN) therapy is widely variable in chronic HCV infected patients, suggesting that HCV has evolved mechanisms to suppress and evade innate immunity responsible for its control and elimination. Adenosine deaminase acting on RNA 1 (ADAR1) is a relevant factor in the regulation of the innate immune response. The loss of ADAR1 RNA-editing activity and the resulting loss of inosine bases in RNA are critical in producing aberrant RLR-mediated innate immune response, mediated by RNA sensors MDA5 and RIG-I. Here, we describe ADAR1 role as a regulator of innate and antiviral immune function in HCV infection, both in vitro and in patients. Polymorphisms within ADAR1 gene were found significantly associated to poor clinical outcome to HCV therapy and advanced liver fibrosis in a cohort of HCV and HIV-1 coinfected patients. Moreover, ADAR1 knockdown in primary macrophages and Huh7 hepatoma cells enhanced IFN and IFN stimulated gene expression and increased HCV replication in vitro. Overall, our results demonstrate that ADAR1 regulates innate immune signaling and is an important contributor to the outcome of the HCV virus-host interaction. ADAR1 is a potential target to boost antiviral immune response in HCV infection.
丙型肝炎病毒（HCV）是一种全球流行的传染性病原体。多达 80%的 HCV 感染者无法控制病毒并发展为慢性感染。慢性 HCV 感染患者对干扰素（IFN）治疗的反应差异很大，这表明 HCV 已经进化出抑制和逃避固有免疫的机制，固有免疫负责其控制和消除。作用于 RNA 1 的腺苷脱氨酶（ADAR1）是调节固有免疫反应的相关因素。ADAR1 RNA 编辑活性的丧失以及 RNA 中肌苷碱基的缺失对于产生异常 RLR 介导的固有免疫反应至关重要，该反应由 RNA 传感器 MDA5 和 RIG-I 介导。在这里，我们描述了 ADAR1 在 HCV 感染中的固有和抗病毒免疫功能中的调节作用，包括在体外和患者中。在 HCV 和 HIV-1 合并感染患者的队列中，发现 ADAR1 基因内的多态性与 HCV 治疗的临床不良结局和晚期肝纤维化显著相关。此外，在原代巨噬细胞和 Huh7 肝癌细胞中敲低 ADAR1 可增强 IFN 和 IFN 刺激基因的表达，并增加体外 HCV 复制。总之，我们的研究结果表明，ADAR1 调节固有免疫信号转导，是 HCV 病毒-宿主相互作用结局的重要贡献者。ADAR1 是增强 HCV 感染抗病毒免疫反应的潜在靶点。
