Hepatitis C Virus Induced IL-8 & Inhibition of Interferon

描述（由申请人提供）：丙型肝炎病毒（HCV）感染估计3%的世界人口，是肝脏疾病的重要原因。HCV蛋白、细胞蛋白和信号转导机制之间的相互作用对病毒的复制、持续存在、发病机制和抗病毒治疗的结果具有重要影响。HCV蛋白的突变与IFN治疗的临床反应相关，并影响体内和体外HCV复制。HCV蛋白还抑制干扰素（IFN）的抗病毒作用。我们已经发现HCV NS 5A蛋白诱导促炎CXC趋化因子白细胞介素8（IL-8），其与IFN系统的抑制相关。这一发现的体内意义表现为慢性丙型肝炎患者IL-8水平升高。在HCV复制子系统中，我们还发现HCV复制与IL-8产生增加和IFN诱导的转录应答减弱有关。此外，外源性IL-8刺激HCV复制子中的HCV蛋白产生。在这个建议中，我们假设，HCV诱导的IL-8抑制IFN的抗病毒作用，促进HCV复制，并有助于HCV的发病机制。为了解决这一假设，我们提出了两个具体的目标（SA），以确定HCV诱导IL-8的机制，并确定IL-8的抗IFN活性的机制。SA 1将集中于HCV通过IL-8启动子的转录激活和IL-8 mRNA的稳定化诱导IL-8。SA 2将集中于IL-8介导的IFN诱导的2 '-5'寡腺苷酸合成酶/RNA酶L系统的抑制，以及IL-8诱导的有丝分裂原活化蛋白（MAP）激酶和IFN诱导的STAT-JAK途径之间的串扰。一种新的机制，通过趋化因子的IFN系统的调制特性可能是相关的慢性丙型肝炎和许多其他病毒和非病毒性疾病的发病机制。此外，IL-8或其受体可能被证明是慢性丙型肝炎治疗干预的合适靶点。

DESCRIPTION (provided by applicant): Hepatitis C virus (HCV) infects an estimated 3% of the world's population, and is a significant cause of liver disease. The interactions that occur between HCV proteins, cellular proteins and signal transduction machinery have a significant influence on virus replication, persistence, pathogenesis, and the outcome of antiviral therapy. Mutations in HCV proteins correlate with clinical responses to IFN therapy, and affect HCV replication in vivo and in vitro. HCV proteins also inhibit the antiviral actions of interferon (IFN). We have found that the HCV NS5A protein induces the pro-inflammatory CXC chemokine, interleukin 8 (IL-8), which is associated with inhibition of the IFN system. The in vivo significance of this finding is shown by elevated IL-8 levels in persons with chronic hepatitis C. In the HCV replicon system, we have also found that HCV replication is associated with increased production of IL-8 and attenuated IFN-induced transcriptional responses. Furthermore, exogenous IL-8 stimulates HCV protein production in HCV replicons. In this proposal, we hypothesize that HCV induced IL-8 inhibits the antiviral actions of IFN, promotes HCV replication, and contributes to HCV pathogenesis. To address this hypothesis, we propose 2 specific aims (SA) to determine the mechanisms of HCV induction of IL-8, and to determine the mechanisms of IL-8's anti-IFN activity. SA1 will focus on HCV induction of IL-8 via both transcriptional activation of the IL-8 promoter and stabilization of IL-8 mRNA. SA2 will focus on IL-8 mediated inhibition of the IFN-induced 2'-5' oligoadenylate synthetase/RNase L system, as well as cross-talk between IL-8 induced mitogen activated protein (MAP) kinases and IFN induced STAT-JAK pathways. The characterization of a new mechanism for modulation of the IFN system by a chemokine may be relevant to pathogenesis of chronic hepatitis C and many other viral and non-viral diseases. Moreover, IL-8 or its receptors may prove to be suitable targets for therapeutic intervention in chronic hepatitis C.