Immune Escape Strategies in HCV infection

描述（由申请人提供）：此U19申请为丙型肝炎合作研究中心（HCV CRC）的重点是HCV逃避或抑制宿主免疫反应的机制。下面描述的三个高度相互关联的项目将表征先天性和适应性免疫的多个组成部分，这些组成部分影响是否发生自发消退或病毒持续存在。本提案的具体目标实现了本RFA的几个既定目标，包括但不限于：阐明HCV在初始感染时和慢性感染期间解除调节和逃避宿主免疫应答的机制和关键步骤（例如，HCV蛋白在钝化先天免疫应答中的作用，包括树突细胞成熟）;检查与多次暴露于病毒后慢性HCV的更良性结果相关的免疫应答的作用（例如，在静脉注射吸毒者中），与侵袭性和严重的结果相比;阐明病毒因素在慢性感染的建立和进展速度中的作用;构建原型候选疫苗（或其他新的免疫策略），并在适当的体外和体内模型系统中评估这些疫苗。每个研究者都有持续的合作，并致力于HCV感染中免疫逃避的中心和难题。由此产生的协同作用将使每个实验室的研究人员能够使用没有这种多中心应用程序就无法使用的工具和方法。根据初步数据，本次HCV CRC的总体目标是确定免疫系统如何 可成功预防和根除HCV感染和HCV相关恶性肿瘤。更具体地说，我们假设：1）急性感染后早期自然杀伤细胞和树突状细胞活性的强度与自发清除病毒的相对可能性相关; 2）HCV蛋白对先天性细胞信号转导通路的不同激活和抑制影响急性感染的结果; 3）调节性CD 4 + T细胞的抑制能力（可能由HCV核心与gC 1 R结合介导）抑制保护性抗病毒T细胞免疫的发展。

DESCRIPTION (provided by applicant): This U19 application for a hepatitis C Cooperative Research Center (HCV CRC) focuses on the mechanisms employed by HCV to evade or suppress the host immune response. Three highly inter-related projects described below would characterize multiple components of innate and adaptive immunity that influence whether spontaneous resolution or viral persistence occurs. The specific aims of this proposal fulfill several of the stated aims of this RFA, including but not limited to: elucidate the mechanisms and key steps by which HCV deregulates and evades the host immune response at the time of initial infection and during chronic infection (e.g., the role of HCV proteins in blunting the innate immune response, including dendritic cell maturation); examine the role of immune responses associated with more benign outcome of chronic HCV following multiple exposures to virus (e.g., in intravenous drug users), as compared to aggressive and severe outcomes; elucidate the role of viral factors in the establishment and rate of progression of chronic infection; construct prototype vaccine candidates (or other novel immunotherapeutic strategies) and evaluate these in appropriate in vitro and in vivo model systems. Each of the investigators have ongoing collaborations and are committed to the central and difficult problem of immune evasion in HCV infection. The resulting synergy will allow investigators in each laboratory to use tools and approaches that would not be readily available without this multi-center application. Based on preliminary data, the overall goal of this HCV CRC will be to determine how the immune system can successfully protect against and eradicate HCV infection and HCV-related malignancies. More specifically, we hypothesize that: 1) the strength of natural killer and dendritic cell activity early after acute infection correlates with the relative likelihood of spontaneously eradicating virus; 2) the differential activation and repression of the innate cellular signal transduction pathways by HCV proteins affects the outcome of acute infection; 3) the suppressive ability of regulatory CD4+ T cells (perhaps mediated by HCV core binding to gC1R) inhibits the development of protective antiviral T cell immunity.