Novel type I interferon IL-28A suppresses hepatitis C viral RNA replication.
Novel type I interferon IL-28A suppresses hepatitis C viral RNA replication.
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DOI：
10.1186/1743-422x-2-80
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发表时间：
2005-09-07
期刊：
影响因子：
4.8
通讯作者：
Liu C
中科院分区：
文献类型：
--
作者：
Zhu H;Butera M;Nelson DR;Liu C
基于干扰素α (IFN-α)的治疗是目前批准的慢性丙型肝炎病毒感染的治疗方法。基因1型感染的持续抗病毒反应率约为50%。HCV社区面临的主要挑战是提高抗病毒疗效并减少以ifn α为基础的治疗中常见的副作用。其中一个策略是发现新的干扰素，它可能具有更好的疗效和更少的不良副作用。在本报告中，我们研究了IL-28A (IFN λ2)，一种新型I型IFN，在抑制人类丙型肝炎病毒RNA复制中的作用。我们克隆了IL-28A的人类基因组DNA和cDNA，并利用HCV RNA复制子细胞培养系统对其生物活性进行了评价。结果表明，IL-28A以剂量依赖的方式有效抑制HCV亚基因组RNA复制。用IL-28A治疗人肝癌细胞激活JAK-STAT信号通路，诱导一些干扰素刺激基因（ISGs）的表达，如6-16和1-8U。我们也证实了IL-28A在人肝癌细胞中诱导HLA I类抗原的表达。此外，IL-28A似乎特异性抑制HCV ires介导的翻译。虽然IL-28A受体与IL-10受体共享一个亚基，但IL-10治疗对IL-28A诱导的抗病毒活性没有可检测到的影响。有趣的是，IL-28A可以协同增强IFNα的抗病毒效果。我们的研究结果表明，IL-28A的抗病毒活性与JAK-STAT信号通路的激活和ISGs的表达有关。IL-28A抗病毒活性的有效性及其对IFN-α的协同作用提示IL-28A可能用于治疗HCV慢性感染。
Interferon alpha (IFN-α)-based therapy is the currently approved treatment for chronic hepatitis C viral infection. The sustained antiviral response rate is approximately 50% for genotype-1 infection. The major challenge to the HCV community is to improve antiviral efficacy and to reduce the side effects typically seen in IFNα-based therapy. One of the strategies is to identify new interferons, which may have better efficacy and less undesirable side effects. In this report, we examined the role of IL-28A (IFN λ2), a novel type I IFN, in suppression of human hepatitis C viral RNA replication. We have cloned both the human genomic DNA and cDNA of IL-28A, and evaluated their biological activity using HCV RNA replicon cell culture system. The results show that IL-28A effectively inhibits HCV subgenomic RNA replication in a dose-dependent manner. Treatment of human hepatoma cells with IL-28A activates the JAK-STAT signaling pathway and induces the expression of some interferon-stimulated genes (ISGs), such as 6–16 and 1–8U. We also demonstrate that IL-28A induces expression of HLA class I antigens in human hepatoma cells. Moreover, IL-28A appears to specifically suppress HCV IRES-mediated translation. Although IL-28A receptor shares one subunit with the IL-10 receptor, IL-10 treatment has no detectable effect on IL-28A-induced antiviral activity. Interestingly, IL-28A can synergistically enhance IFNα antiviral efficacy. Our results suggest that IL-28A antiviral activity is associated with the activation of the JAK-STAT signaling pathway and expression of ISGs. The effectiveness of IL-28A antiviral activity and its synergistic effect on IFN-α indicate that IL-28A may be potentially used to treat HCV chronic infection.