Mechanisms of T cell dysfunction in Hepatitis C virus persistence

简介（由申请人提供）：Henry Radziewicz是Emory大学传染病医学专业的一名非常积极的科学家，他的总体目标是发展独立的科学事业，研究项目集中在了解慢性病毒感染（如丙型肝炎病毒（HCV））的发病机制。为什么对HCV的适应性免疫反应在大多数感染者中失败？他的近期目标是通过研究生涯奖（K08）获得资助，这将为教学和研究提供足够的保护时间，以实现这一发展。他的长期目标是随着对慢性病毒性疾病发病机制的进一步了解，发现并测试更好的治疗方法。丙型肝炎病毒感染1.5亿至2亿人，导致慢性肝炎、肝硬化和肝细胞癌。它已经成为美国肝移植的主要原因。由于致残的副作用，目前的HCV治疗方法很难耐受，需要长期治疗，并且在美国，只有大约一半的主要基因型治疗患者成功。需要更好的治疗方法。最近，B7/CD28共抑制分子家族的几个新成员被发现，并可能在调节慢性病毒感染的免疫反应中发挥重要作用。一对分子PD-1及其配体PD-L1在慢性小鼠LCMV感染的免疫应答中发挥了关键作用。阻断PD-1/PD-L1增强了该模型中耗竭T细胞的反应，治疗小鼠能够清除血清、肝脏和肺部的感染。我们假设在大多数感染患者中无法清除HCV病毒血症是由于PD-1/PD-L1共抑制系统的过度表达。在获得研究生涯奖的同时，Henry希望在慢性HCV患者中评估该系统，并测试抑制该系统是否能改善HCV特异性CD8+ T细胞的功能。在顶级科学家Arash Grakoui和Rafi Ahmed的指导下，Henry提出的四年计划将包括一年的基础免疫学和信号转导教学，然后是三年的实验室研究。埃默里大学致力于帮助亨利实现成为顶尖科学家的目标，埃默里大学和疫苗研究中心的环境是一个年轻科学家蓬勃发展的绝佳环境。

DESCRIPTION (provided by applicant): Henry Radziewicz is a highly motivated scientist at Emory University with a specialty in Infectious Diseases Medicine, whose overall goal is to develop an independent scientific career with a research program focused on understanding the pathogenesis of chronic viral infections such as hepatitis C virus (HCV). Why does the adaptive immune response to HCV fail in the majority of infected persons? His immediate goal is to receive funding through a research career award (K08) that will enable sufficient protected time for didactics and research to enable this development. His long-term goal is to discover and test better treatments of chronic viral illness with the improved understanding of their pathogenesis. HCV infects 150-200 million persons and causes chronic hepatitis, cirrhosis, and hepatocellular carcinoma. It has become the major cause of liver transplantation in the United States. Current therapies for HCV are very difficulty to tolerate due to disabling side-effects, require prolonged treatment, and are only successful in approximately half of treated patients for the major genotype in the US. Better therapies are needed. Recently, several new members of the B7/CD28 family of co-inhibitory molecules have been discovered, and may play important roles in modulating the immune responses to chronic viral infections. One pair of molecules, PD-1 and its ligand PD-L1 has demonstrated a critical role in the immune response to chronic murine LCMV infection. Blockade of PD-1/PD-L1 enhanced the response of exhausted T cells in this model, and treated mice were able to clear infection from serum, liver, and lung. We hypothesize that an inability to clear HCV viremia in the majority of infected patients is due to overexpression of the PD-1/PD-L1 co-inhibitory system. In conjunction with a research career award, Henry would like to evaluate this system in humans with chronic HCV, and to test if inhibiting this system improves the function of HCV specific CD8+ T cells. Guided by top scientists, Arash Grakoui and Rafi Ahmed, Henry's proposed 4-year program will include one year of didactics in basic immunology and signal transduction, followed by three lab-based, research concentrated years. Emory University is committed to help Henry reach his goal of becoming a top scientist, and the environment at Emory and the Vaccine Research Center is a wonderful environment for a young scientist to flourish.