Baltimore Acute Hepatitis C Cooperative Center

巴尔的摩急性丙型肝炎合作中心

• 批准号: 8625266
• 负责人: ANDREA L COX
• 金额: $ 75.09万
• 依托单位: JOHNS HOPKINS UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2010
• 资助国家: 美国
• 起止时间: 2010-04-15 至 2016-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8625266
• 关键词: Acute; Acute Hepatitis C; Baltimore; Cells; Chronic; Chronic Phase; Complex; Detection; Development; Diagnosis; Epitopes; Evaluation; Evolution; Frequencies; Future; Generations; Hepatitis C; Hepatitis C virus; Human; Immune; Immune response; Immunity; Immunologics; Immunotherapy; Infection; Infection Control; Injecting drug user; Instruction; Mediating; Mutation; Natural Immunity; Outcome; Patients; Polymerase; Primates; Reaction Time; Research; Resources; Role; T cell response; T-Lymphocyte; United States; Virus; Virus Diseases; anti-hepatitis C; base; cohort; high risk; liver transplantation; prevent; prophylactic; response; therapeutic vaccine; vaccine development

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.

描述（由申请方提供）：HCV感染诱导人的复杂免疫应答，其特征在于诱导先天免疫，随后是细胞介导的和体液适应性免疫应答。在约20%的急性HCV感染中，抗HCV免疫应答控制感染。对人类和灵长类动物HCV感染的分析表明，清除与HCV表位特异性的稳健的CD4和CD8 T细胞应答相关。虽然中和体液反应的产生在HCV感染中也可能很重要，但它们在清除中的最终作用仍有待确定。了解免疫逃避机制，使HCV在大多数情况下发展和维持慢性感染是至关重要的预防性和治疗性疫苗的开发。HCV具有高度易错的聚合酶，具有相应的高突变率，使HCV能够迅速逃避正在发生的免疫反应。因此，完整的理解成功的免疫反应，HCV的逃避和逃避消毒免疫的机制，需要从初始感染的时间，直到结果确定的HCV序列和HCV特异性适应性免疫反应的系列分析。除了表位特异性T细胞和体液应答的特异性定量分析的技术复杂性之外，HCV免疫的研究还由于急性感染通常无症状并且因此通常未被检测到的事实而进一步复杂化。因此，绝大多数HCV感染患者在其慢性期被诊断，在对急性感染产生关键免疫应答很久之后。该中心包括一个独特的注射吸毒者队列，每月随访一次，从而允许高频率检测新发急性HCV感染和纵向评估感染结果。因此，拟议的研究将独特的患者资源与HCV特异性T细胞和体液免疫应答以及HCV序列进化研究的领导者结合在一起。队列和序列进化以及免疫学专业知识的结合使所提出的项目可行，可能增加对人类慢性病毒感染的理解并促进免疫疗法的发展。