Immune Control and Evasion During Acute HCV Infection

描述（由申请人提供）：HCV在世界范围内感染1.7亿人，在发达国家和发展中国家发病率很高。丙型肝炎病毒感染的治疗方法最近有所改善，但在许多人身上仍然失败，并且世界上大多数感染者无法获得治疗。因此，了解对这种感染的自然免疫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HCV感染期间的早期事件，因为这是观察到病毒血症自发清除发生的唯一时间。我们对急性人类HCV感染早期事件的理解是有限的，因为很难确定急性感染者进行研究，也因为以前用于分析免疫反应和病毒进化的方法存在局限性。与巴西里约热内卢Oswaldo Cruz研究所的病毒性肝炎国家参考中心一起，我们已经确定了30多例急性症状型丙型肝炎病例。此外，还将招募无症状疾病患者。除了这些通过非静脉吸毒机制感染的受试者外，我们还在研究被监禁静脉吸毒者的急性HCV感染问题，这是一个重要的服务不足的人群，具有HCV暴露的高风险。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性的免疫检测方法，允许对hcv特异性t细胞免疫反应进行纵向定性和定量评估。我们将通过自体病毒的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HCV的先天免疫反应的潜在缺陷是该应用的另一个重点，我们已经开始在该中心之外的合作，研究这里未涉及的其他机制，例如中和抗体的作用。总之，我们将收集大量急性HCV感染患者的全面临床、免疫学和病毒学数据，这些患者代表了不同的传播途径、不同的临床表现和不同的感染结局。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大大提高对病毒控制和持续存在的机制的理解，并将促进未来对HCV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.