Inhibition of Hepatitis C Virus Infection by Interferon-induced Transmembrane Pro

描述(申请人提供)：全球有超过1.7亿人慢性感染丙型肝炎病毒，使他们面临肝功能衰竭和肝癌的风险。这个 目前丙型肝炎的治疗包括聚乙二醇化干扰素和利巴韦林，但这种治疗只对大约一半的患者有效。最近批准的蛋白酶抑制剂的治疗方案有所改善，但治愈率仍然不够理想。此外，蛋白酶抑制剂增加了已经很大的副作用，病毒耐药性正迅速成为一个令人担忧的问题。由于最新的护理标准仍然依赖于以干扰素为基础的治疗，了解干扰素治疗引起的抗病毒状态对于改进治疗发展至关重要。干扰素诱导的抗病毒作用背后的机制还不完全清楚，特别是关于干扰素刺激基因(ISGs)具有抗病毒效应功能的机制。我们对识别具有抑制丙型肝炎病毒感染能力的ISG很感兴趣 长期目标是为更直接和更成功的抗丙型肝炎病毒疗法发现新的靶点。我们已经确定干扰素诱导的跨膜蛋白(IFITM)家族分子在细胞培养系统中对丙型肝炎病毒具有抑制作用。IFITM1改变了丙型肝炎病毒的细胞受体CD81与其他丙型肝炎病毒辅助受体和肝紧密连接部分的联系。我们的下一个目标是在丙型肝炎病毒感染的背景下表征这些分子的生物学功能，特别是IFITM1的生物学功能，并确定IFITM1的机制。我们建议通过以下目标来实现这些目标：(1)确定IFITM表达影响丙型肝炎病毒复制周期的阶段(S)和(2)确定IFITM1调节CD81依赖的复合体的分子功能。总之，提出的实验将描述一组干扰素诱导的效应分子的功能，并确定它们在干扰素治疗后建立的抗病毒状态中的作用。这些 研究将对干扰素治疗如何成功抑制丙型肝炎病毒的机制提供更完整的理解，从而实现更有针对性的治疗方法。 公共卫生相关性：丙型肝炎病毒慢性感染超过1.7亿人，导致包括肝癌在内的大量肝脏疾病。目前丙型肝炎感染的治疗方法只对大约一半的感染患者有效，这使得开发新的治疗方法是必要的。更好地了解当前疗法的抗病毒功能将确定潜在的新药靶点。

DESCRIPTION (provided by applicant): Over 170 million people worldwide are chronically infected with hepatitis C virus (HCV), placing them at risk for liver failure and liver cancer. The current treatment for HCV consists of pegylated interferon alpha (IFN-a) with ribavirin, yet this treatment is only effective in about half of all patients. Therapeutic options have improved with the recently approved protease inhibitors, yet cure rates remain less than ideal. Additionally, protease inhibitors add to already substantial side effects, and viral resistance is rapidly becoming a concern. As the updated standard of care still relies on IFN-based therapy, an understanding of the antiviral state induced by IFN treatment is crucial for improvements in therapeutic developments. The mechanisms behind IFN-induced antiviral actions are not fully understood, particularly in regards to which interferon-stimulated genes (ISGs) have antiviral effector functions. We are interested in identifying ISGs with the ability to inhibit HCV infection with the long-term goal of discovering novel targets for more directed and successful anti-HCV therapies. We have identified the interferon-induced transmembrane protein (IFITM) family of molecules as having inhibitory actions on HCV in cell culture systems. IFITM1 alters the association of a cellular receptor for HCV, CD81, with other HCV coreceptors and components of the hepatic tight junction. Our next goal is to characterize the biological functions of these molecules, particularly that of IFITM1, in the context of HCV infection and to determine the mechanism by which IFITM1. We propose to accomplish these goals through the following aims: (1) Determine the stage(s) of the HCV replication cycle affected by IFITM expression and (2) Identify the molecular function by which IFITM1 regulates CD81-dependent complexes. Together, the experiments proposed will describe the function of a set of IFN-induced effector molecules and identify their role in the antiviral state established following IFN treatment. These studies will provide a more complete understanding as to the mechanism of how successful IFN treatment inhibits HCV to allow for more targeted therapeutic approaches. PUBLIC HEALTH RELEVANCE: Hepatitis C virus chronically infects over 170 million people, leading to significant levels of liver disease including liver cancer. Current treatments for hepatitis C infection only work in about half of infected patients, making development of novel therapies a necessity. A better understanding of antiviral functions of current therapies will identify potential new drug targets.