Department of Physiology, Guilin Medical University, Guilin, 541004, Guangxi, China.
Department of Microbiology, Guilin Medical University, Guilin, 541004, Guangxi, China; Key Laboratory of Tumor Immunology and Microenvironmental Regulation, Guilin Medical University, Guilin, 541004, Guangxi, China.
Virus Res. 2021 Apr 15;296:198336. doi: 10.1016/j.virusres.2021.198336. Epub 2021 Feb 9.
Hepatitis C virus (HCV) can cause chronic lifelong infections in humans, resulting in sustained hepatic inflammation, liver cirrhosis, and hepatocellular carcinoma. The clearance of HCV infections is dependent upon effective and coordinated innate and adaptive antiviral immune responses. However, HCV has evolved a range of strategies that enable it to evade or overcome the host immune response, enabling the virus to persist in susceptible hosts through mechanisms that remain to be fully clarified. Herein, we describe a novel mechanism whereby HCV can evade immune surveillance by activating microRNA (miR)-125a. Hepatocytes upregulate miR-125a following HCV infection, and serum from HCV-infected patients similarly exhibits the upregulation of this miRNA. We found that miR-125a is able to target and suppress the expression of two key genes associated with the interferon (IFN) signaling pathway - mitochondrial antiviral signaling (MAVS) and TNF receptor-associated factor 6 (TRAF6). Disrupting the expression of these genes can in turn compromise type I IFN responses to HCV. Together, our data reveal that HCV infection results in the upregulation of miR-125a, which negatively regulates IFN signaling via inhibiting the expression of MAVS and TRAF6, thereby enabling the virus to evade innate antiviral immunity. Targeting this pathway may thus represent an efficient approach to treating HCV and bolstering antiviral immune responses in infected patients.
丙型肝炎病毒（HCV）可在人类中引起慢性终身感染，导致持续的肝炎症、肝硬化和肝细胞癌。HCV 感染的清除依赖于有效的先天和适应性抗病毒免疫反应。然而，HCV 已经进化出一系列策略，使其能够逃避或克服宿主的免疫反应，使病毒能够通过尚未完全阐明的机制在易感宿主中持续存在。在此，我们描述了一种新的机制，即 HCV 通过激活 microRNA（miR）-125a 来逃避免疫监视。HCV 感染后肝细胞上调 miR-125a，HCV 感染患者的血清也表现出这种 miRNA 的上调。我们发现 miR-125a 能够靶向并抑制两种与干扰素（IFN）信号通路相关的关键基因 - 线粒体抗病毒信号（MAVS）和 TNF 受体相关因子 6（TRAF6）的表达。这些基因表达的破坏反过来又会损害 HCV 对 I 型 IFN 的反应。总之，我们的数据表明，HCV 感染导致 miR-125a 的上调，通过抑制 MAVS 和 TRAF6 的表达，负调控 IFN 信号，从而使病毒逃避先天抗病毒免疫。因此，靶向该途径可能是治疗 HCV 和增强感染患者抗病毒免疫反应的有效方法。
