Immune Control and Evasion during Acute HCV Infection

HCV感染全世界1.7亿人，并在发达国家和发展中国家引起显著的发病率。 国家HCV感染的治疗最近有所改善，但在许多人中仍然失败，并且无法获得。 全球感染人数最多。因此，了解对这种感染的天然免疫力， 开发预防性疫苗仍然是迫切的目标。为此，必须更好地了解 急性HCV感染期间的早期事件，因为这是病毒血症自发清除的唯一时间 已经被观察到发生。 我们对急性人类HCV感染早期事件的理解是有限的，因为难以确定HCV感染的早期事件。 确定急性感染的人进行研究，并由于以前的限制，在所使用的方法， 分析免疫反应和病毒进化与国家病毒性肝炎参考中心一起 在巴西里约热内卢的奥斯瓦尔多·克鲁兹研究所，我们已经发现了30多例急性 症状性HCV。此外，还将招募无症状疾病的人。除了这些 受试者都是通过静脉注射药物以外的机制感染的，我们也在研究 静脉注射吸毒者急性HCV感染，这是一个重要的高风险低服务人群 HCV暴露。为了研究导致病毒根除或持续存在的机制， 灵敏和特异的免疫测定，允许纵向定性和定量评估 HCV特异性T细胞免疫反应。我们将通过自体的全长测序来补充这些研究。 确定免疫应答对病毒进化的影响以及病毒逃逸的机制 和适应。针对HCV的先天免疫应答的潜在缺陷是本申请的另一个焦点， 我们已经开始在该中心以外的合作，以调查未涵盖的其他机制， 这里，例如中和抗体的作用。 总之，我们将从一个大的群体中收集全面的临床，免疫学和病毒学数据。 急性HCV感染的个体，代表不同的传播途径，不同的临床表现 和不同的感染结果。我们有信心，综合体的全面描述 人类免疫系统和病毒之间的相互作用将导致对 涉及病毒控制和持久性的机制，将有助于未来的预防和治疗 针对HCV感染的干预措施。

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.