Immune Control and Immune Evasion during Acute Hepatitis C Virus Infection

描述(申请人提供)：丙型肝炎病毒感染全球1.7亿人，并在发达国家和发展中国家造成重大发病率。丙型肝炎病毒感染的治疗方法最近有所改善，但在许多人中仍然无效，全世界大多数感染者都无法使用。因此，了解对这种感染的自然免疫力和开发预防性疫苗仍然是迫切的目标。为此，有必要更好地了解急性丙型肝炎病毒感染期间的早期事件，因为这是观察到病毒血症自发清除的唯一时间。我们对急性人类丙型肝炎病毒感染早期事件的了解是有限的，这是因为识别急性感染者进行研究的困难，以及先前用于分析免疫反应和病毒进化的方法的局限性。与位于巴西里约热内卢的奥斯瓦尔多·克鲁兹研究所的国家病毒性肝炎参考中心一起，我们已经确定了30多例急性症状丙型肝炎病例。此外，无症状性疾病的人也将被招募。除了这些都是通过静脉注射药物以外的其他途径感染的受试者外，我们还在研究被监禁的静脉注射吸毒者的急性丙型肝炎感染问题，这是一个重要的服务不足的人群，接触丙型肝炎病毒的风险很高。为了研究导致病毒根除或持续存在的机制，我们开发了高度敏感和特异的免疫学检测方法，允许对丙型肝炎病毒特异性T细胞免疫反应进行纵向、定性和定量评估。我们将通过对自体病毒进行全长测序来补充这些研究，以确定免疫反应对病毒进化的影响以及病毒逃逸和适应的机制。针对丙型肝炎病毒的先天免疫反应的潜在缺陷是这项应用的另一个重点，我们已经开始了该中心以外的合作，以研究这里没有介绍的其他机制，例如中和抗体的作用。总而言之，我们将从一大群急性丙型肝炎患者中收集全面的临床、免疫学和病毒学数据，代表不同的传播途径、不同的临床表现和不同的感染结果。我们相信，对人类免疫系统和病毒之间复杂相互作用的全面描述将显著提高对病毒控制和持久性所涉及的机制的了解，并将促进未来对丙型肝炎病毒感染的预防和治疗干预。

DESCRIPTION (provided by applicant): HCV infects 170 million persons worldwide and causes significant morbidity in developed and developing countries. Therapies for HCV infection have improved recently, but still fail in many persons and are unavailable for most infected individuals worldwide. Therefore understanding natural immunity to this infection and the development of prophylactic vaccines remain urgent goals. To this end, it will be essential to better understand the early events during acute HCV infection, as this is the exclusive time at which spontaneous clearance of viremia has been observed to occur. Our understanding of the early events during acute human HCV infection is limited because of the difficulties in identifying persons with acute infection for study, and because of previous limitations in the methodologies used to analyze the immune response and viral evolution. Together with the National Reference Center for Viral Hepatitis at the Oswaldo Cruz Institute in Rio de Janeiro/Brazil we have already identified more than 30 cases of acute symptomatic HCV. Furthermore, persons with non-symptomatic disease will also be recruited. In addition to these subjects who were all infected through mechanisms other than iv drug use, we also are studying the problem of acute HCV infection in incarcerated intravenous drug users, an important underserved population with a high risk of HCV exposure. To study the mechanisms leading to viral eradication or persistence we have developed highly sensitive and specific immunologic assays that allow for the longitudinal qualitative and quantitative assessment of HCV-specific T-cell immune responses. We will complement these studies by full-length sequencing of autologous virus to determine the impact of the immune response on viral evolution as well as mechanisms of viral escape and adaptation. Potential deficits in the innate immune response against HCV are another focus of this application, and we have already started collaborations beyond this Center to investigate additional mechanisms not covered here, e.g. the role of neutralizing antibodies. In summary, we will collect comprehensive clinical, immunological and virological data from a large group of individuals with acute HCV infection, representing different routes of transmission, different clinical presentations and different outcomes of infection. We are confident that the comprehensive description of the complex interactions between human immune system and the virus will result in a significantly improved understanding of the mechanisms involved in viral control and persistence and will facilitate future preventative and therapeutic interventions against HCV infection.