Molecular analysis of HCV T cell responses

丙型肝炎感染是一个主要的世界性健康问题，仅在美国就有300-400万人感染。感染的长期后遗症包括慢性肝炎、肝硬变和肝细胞癌。这些并发症的规模的一个原因是，大约70%的急性感染会导致慢性化。为了开发有效的疫苗，了解导致感染解决的因素将是至关重要的。人们认为，免疫系统未能清除感染的大部分时间是由于极端情况，认为免疫系统未能清除感染的大部分时间是由于病毒RNA基因组的极端变异性。以类似于HIV-1的方式，这种病毒以被称为准种的相关序列的混合物的形式存在，这些准种能够在免疫选择压力下快速进化，从而逃避宿主的免疫防御。虽然与清除相关的免疫反应的性质仍然难以捉摸，但似乎强烈的广泛定向的辅助性和细胞毒性T淋巴细胞(CTL)反应有利于清除。黑猩猩模型提供了一个对自然感染进行详细免疫学分析的独特机会。该计划项目的目标是同时评估急性丙型肝炎病毒感染过程中丙型肝炎病毒特异性免疫反应和准种进化。精心设计的T细胞亚群耗尽实验将确定控制病毒复制的免疫反应及其对病毒进化的影响。项目2将评估这些免疫反应的T细胞受体谱系，并应用强大的分子技术纵向跟踪感染动物肝脏和外周血中丙型肝炎病毒特异性T细胞克隆的持久性。我们还将通过急性和慢性感染过程中T细胞恢复期的耗尽来跟踪TCR转录本的流行情况。这些实验将为细胞介导的免疫反应在控制丙型肝炎病毒复制中的作用提供更清晰的图景。

Hepatitis C infection is a major worldwide health problem, infection 3-4 million people in the USA alone. The long-term sequelae of infection include chronic hepatitis, cirrhosis, and hepatocellular carcinoma. One reason for the scale of these complications is that approximately 70% of acute infections lead to chronicity. In order to develop an effective vaccine it will be critical to understand the factors that lead to resolution of infection. It is thought that the failure of the immune system to clear infection the majority of the time is due to the extreme is thought that the failure of the immune system to clear infection the majority of the time is due to the extreme mutability of the virus RNA genome. In a manner similar to HIV-1, this virus exists as a mixture of related sequences termed quasispecies that are able to rapidly evolve under immune selection pressure and hereby escape host immune defenses. Although the nature of the immune responses that correlate with clearance remain elusive, it appears that vigorous broadly directed helper and cytotoxic T lymphocyte (CTL) responses favor resolution. The Chimpanzee model offers a unique opportunity to perform a detailed immunologic analysis of natural infection. The goal of this program project is to simultaneously evaluate HCV-specific immune responses and quasispecies evolution over the course of acute HCV infection. Carefully designed T cell subset depletion experiments will determine the immune responses that control viral replication and the impact they have on viral evolution. Project 2 will evaluate the T cell receptor repertoire of these immune responses, and apply powerful molecular techniques to longitudinally track the persistence of HCV-specific T cell clones in liver and peripheral blood of infected animals. We will also track the prevalence of TCR transcripts through the depletion of recovery phase of T cells over the course of acute and chronic infection. These experiments will provide a clearer picture of the role of cell-mediated immune responses in the control of HCV replication.