Immune Escape Strategies in HCV infection

描述（由申请人提供）：本U19申请的丙型肝炎合作研究中心（HCV CRC）主要研究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描述先天免疫和适应性免疫的多个组成部分，这些组成部分影响是自发消退还是病毒持续存在。该提案的具体目标实现了该RFA的几个既定目标，包括但不限于：阐明HCV在初始感染和慢性感染期间解除和逃避宿主免疫反应的机制和关键步骤（例如，HCV蛋白在钝化先天免疫反应中的作用，包括树突状细胞成熟）；在多次接触病毒（例如静脉注射吸毒者）后，与侵袭性和严重后果相比，检查与慢性HCV良性结局相关的免疫反应的作用；阐明病毒因子在慢性感染的发生和进展中的作用；构建候选疫苗原型（或其他新的免疫治疗策略），并在适当的体外和体内模型系统中对其进行评估。每个研究人员都有持续的合作，并致力于解决丙型肝炎病毒感染中免疫逃避的核心和困难问题。由此产生的协同作用将允许每个实验室的研究人员使用工具和方法，如果没有这个多中心应用程序，这些工具和方法将不容易获得。基于初步数据，这种HCV CRC的总体目标将是确定免疫系统如何

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.