Institut de Recherche en Immunologie et en Cancérologie (IRIC), Université de Montréal, Québec, Canada H3T 1J4.
J Hepatol. 2012 Jan;56(1):70-7. doi: 10.1016/j.jhep.2011.07.017. Epub 2011 Aug 9.
BACKGROUND & AIMS: Innate sensing of viral infection activates a global defense response including type I interferon (IFN) and IFN-stimulated genes (ISGs) expression. We previously reported that HCV NS3/4A protease, an essential protein in viral polyprotein processing, can abrogate antiviral signaling pathways and effectors' response when ectopically expressed in human hepatocytes by cleaving antiviral adaptor CARDIF. However, whether HCV mediates evasion of innate immunity in patients with chronic infection remains unclear.
In this study, paired liver biopsies and corresponding purified hepatocytes of chronic hepatitis C patients and controls were subjected to transcriptional analysis of selected innate immune genes and to CARDIF protein detection.
We report that an antiviral response is largely supported by infected hepatocytes as demonstrated by upregulation of the representative antiviral genes ISG15, ISG56, and OASL as well as chemokines genes CXCL9, CXCL10, and CXCL11 measured in both HCV-derived liver biopsies and hepatocytes; that the mRNA levels of these indicator ISGs correlate inversely with HCV RNA level; and more importantly that expression of the early responsive IRF3-dependent genes type I IFNβ, type III IL28A/IL29, and chemokine CCL5 are severely compromised and associated to a global decrease of CARDIF adaptor in infected hepatocytes.
Altogether the data argue for a strong viral strategy that counteracts the host's early antiviral response of hepatocytes from chronic patients without impairing ISGs induced via classical IFN pathway.
病毒感染的先天感应会激活包括 I 型干扰素（IFN）和 IFN 刺激基因（ISG）表达在内的全局防御反应。我们之前曾报道，HCV NS3/4A 蛋白酶是病毒多蛋白加工过程中的必需蛋白，当它在人肝细胞中通过切割抗病毒接头 CARDIF 异位表达时，可以阻断抗病毒信号通路和效应子的反应。然而，HCV 是否在慢性感染患者中介导对先天免疫的逃避仍不清楚。
在这项研究中，对慢性丙型肝炎患者和对照者的配对肝活检和相应的纯化肝细胞进行了选定的先天免疫基因的转录分析，并检测了 CARDIF 蛋白。
我们报告说，抗病毒反应主要由受感染的肝细胞支持，这表现为代表性抗病毒基因 ISG15、ISG56 和 OASL 的上调，以及在 HCV 衍生的肝活检和肝细胞中测量的趋化因子基因 CXCL9、CXCL10 和 CXCL11 的上调；这些指示 ISG 的 mRNA 水平与 HCV RNA 水平呈负相关；更重要的是，早期反应性依赖 IRF3 的基因 I 型 IFNβ、III 型 IL28A/IL29 和趋化因子 CCL5 的表达严重受损，并与感染肝细胞中 CARDIF 接头的整体减少相关。
总之，这些数据表明，病毒存在一种强大的策略，可以对抗慢性患者肝细胞的宿主早期抗病毒反应，而不会损害通过经典 IFN 途径诱导的 ISGs。
