Hepatitis C Virus Induced IL-8 & Inhibition of Interferon

描述(申请人提供)：丙型肝炎病毒(丙型肝炎病毒)感染约3%的世界人口，是肝脏疾病的重要原因。丙型肝炎病毒蛋白、细胞蛋白和信号转导机制之间的相互作用对病毒的复制、持久性、发病机制和抗病毒治疗的结果有重要影响。丙型肝炎病毒蛋白的突变与干扰素治疗的临床反应相关，并影响体内和体外的丙型肝炎病毒复制。丙型肝炎病毒蛋白也抑制干扰素的抗病毒作用。我们发现，丙型肝炎病毒NS5A蛋白可诱导促炎症的CXC趋化因子白介素8(IL-8)，这与抑制干扰素系统有关。这一发现的体内意义体现在慢性丙型肝炎患者体内IL-8水平的升高。在丙型肝炎病毒复制子系统中，我们还发现，丙型肝炎病毒复制与IL-8的产生增加和干扰素诱导的转录反应减弱有关。此外，外源性IL-8可刺激丙型肝炎病毒复制子中丙型肝炎病毒蛋白的产生。在这个方案中，我们假设丙型肝炎病毒诱导的IL-8抑制了干扰素的抗病毒作用，促进了丙型肝炎病毒的复制，并参与了丙型肝炎病毒的发病。为了解决这一假说，我们提出了两个特异性靶点(SA)来确定丙型肝炎病毒诱导IL-8的机制，并确定IL-8‘S抗干扰素的机制。SA1将专注于通过转录激活IL-8启动子和稳定IL-8 mRNA来诱导丙型肝炎病毒诱导IL-8。SA2将重点研究IL-8对干扰素诱导的2‘-5’寡腺苷合成酶/核糖核酸酶L系统的抑制作用，以及IL-8诱导的丝裂原活化蛋白(MAP)激酶和干扰素诱导的STAT-JAK通路之间的相互作用。趋化因子调节干扰素系统的新机制的特征可能与慢性丙型肝炎和许多其他病毒和非病毒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.