Hepatitis C Virus Induced IL-8 & Inhibition of Interferon

描述（由申请人提供）：丙型肝炎病毒（HCV）感染估计占世界人口的3%，并且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发生的相互作用对病毒的复制、持久性、发病机制和抗病毒治疗的结果有重要影响。HCV蛋白突变与IFN治疗的临床反应相关，并影响体内和体外的HCV复制。HCV蛋白也抑制干扰素（IFN）的抗病毒作用。我们发现HCV NS5A蛋白诱导促炎CXC趋化因子白介素8 (IL-8)，这与IFN系统的抑制有关。慢性丙型肝炎患者IL-8水平升高表明了这一发现的体内意义。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诱导的转录反应减弱有关。此外，外源性IL-8刺激HCV复制子中HCV蛋白的产生。在本研究中，我们假设HCV诱导的IL-8抑制IFN的抗病毒作用，促进HCV复制，并参与HCV的发病机制。为了解决这一假设，我们提出了两个特定的目的（SA）来确定HCV诱导IL-8的机制，并确定IL-8抗ifn活性的机制。SA1将通过IL-8启动子的转录激活和IL-8 mRNA的稳定，专注于HCV诱导IL-8。SA2将专注于IL-8介导的IFN诱导的2‘-5’寡聚腺苷酸合成酶/RNase L系统的抑制，以及IL-8诱导的丝裂原活化蛋白（MAP）激酶和IFN诱导的STAT-JAK通路之间的串扰。通过趋化因子调节IFN系统的新机制的表征可能与慢性丙型肝炎和许多其他病毒性和非病毒性疾病的发病机制有关。此外，IL-8或其受体可能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.