Baltimore Acute Hepatitis C Cooperative Center

描述(申请人提供)：人类感染丙型肝炎病毒可诱导一种复杂的免疫反应，其特征是诱导先天免疫，然后是细胞介导和体液适应性免疫反应。在-20%的急性丙型肝炎病毒感染中，抗-丙型肝炎病毒免疫反应控制感染。对人类和灵长类丙型肝炎病毒感染的分析表明，清除与针对丙型肝炎病毒表位的强大的CD4和CDS T细胞反应有关。尽管中和体液反应的产生在丙型肝炎病毒感染中可能也很重要，但它们在清除中的最终作用仍有待确定。了解免疫逃避的机制，使丙型肝炎病毒在大多数病例中发展和维持慢性感染，对于预防和治疗性疫苗的开发至关重要。丙型肝炎病毒具有高度易出错的聚合酶，具有相应的高突变率，使丙型肝炎病毒能够迅速逃脱正在形成的免疫反应。因此，要完全了解丙型肝炎病毒的成功免疫应答及其逃避灭菌免疫的机制，需要对丙型肝炎病毒序列和丙型肝炎病毒特异性获得性免疫应答进行一系列分析，从最初感染到结果确定。除了表位特异性T细胞和体液反应的特异性定量分析的技术复杂性外，由于急性感染通常没有症状，因此通常无法检测到，因此对丙型肝炎免疫的研究进一步复杂化。因此，绝大多数感染丙型肝炎病毒的患者是在慢性期被诊断出来的，这是在对急性感染产生关键免疫反应很久之后。该中心包括每月跟踪注射吸毒者的独特队列，从而能够高频检测从头开始的急性丙型肝炎病毒感染并对感染结果进行纵向评估。因此，这项拟议的研究汇集了独特的患者资源，在丙型肝炎病毒特异性T细胞和体液免疫反应以及丙型肝炎病毒序列进化的研究中处于领先地位。队列、序列进化和免疫学专业知识的结合使拟议的项目具有可行性，有可能增加对人类慢性病毒感染的了解，并促进免疫疗法的开发。

DESCRIPTION (provided by applicant): HCV infection of humans induces a complex immune response characterized by induction of innate immunity followed by both cell mediated and humoral adaptive immune responses. In -20% of acute HCV Infections, the anti-HCV Immune response controls the infection. Analysis of both human and primate HCV infection indicates that clearance is associated with robust CD4 and CDS T cell responses specific for HCV epitopes. Although the generation of neutralizing humoral responses is also likely important in HCV infection, their ultimate role in clearance remains to be determined. Understanding the mechanisms of immune evasion that allow HCV to develop and maintain chronic infection in the majority of cases is critical to prophylactic and therapeutic vaccine development. HCV has a highly error-prone polymerase with a correspondingly high mutation rate, allowing HCV to rapidly escape developing immune responses. Therefore, complete understanding of the successful immune response to HCV with its mechanisms of evasion and escape from sterilizing immunity requires serial analysis of both HCV sequence and HCV-specific adaptive immune responses from the time of initial infection until outcome is determined. In addition to the technical complexity of specific quantitative analysis of epitope specific T cell and humoral responses, the study of HCV immunity is further complicated by the fact that acute infection is generally asymptomatic and therefore typically not detected. The vast majority of HCV infected patients are therefore diagnosed during their chronic phase, long after the critical immune responses to acute infection are generated. The Center includes a unique cohort of injection drug users followed on a monthly basis, thereby allowing high frequency detection of de novo acute HCV infection and longitudinal evaluation of infection outcome. Thus, the proposed research brings together unique patient resources with leaders in the study of HCV-specific T cell and humoral immune responses and HCV sequence evolution. The combination of cohort and sequence evolution and immunologic expertise make the proposed projects feasible, potentially increasing understanding of human chronic viral infections and enhancing development of immunotherapies.