Mechanisms driving breadth of HCV neutralization during repeated control of acute infection in humans

在反复控制人类急性感染期间推动 HCV 中和广度的机制

• 批准号: 9900737
• 负责人: STUART C RAY
• 金额: $ 17.52万
• 依托单位: JOHNS HOPKINS UNIVERSITY
• 依托单位国家: 美国
• 资助国家: 美国
• 起止时间: 至
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/9900737
• 关键词: Acute; Acute Hepatitis C; Affinity; Antibody Response; Antibody Specificity; Automobile Driving; B cell repertoire; B-Lymphocytes; Binding; CD4 Positive T Lymphocytes; Clinical; Collaborations; Data; Development; Doctor of Medicine; Epitopes; Evolution; Exposure to; Generations; Genetic Variation; Genome; Goals; Hepatitis C; Hepatitis C Vaccine; Hepatitis C virus; Human; Human papillomavirus 16 E1 protein; Immune response; Immunoglobulin Somatic Hypermutation; Individual; Infection; Inflammation; Inflammatory; Investigation; Knowledge; Lead; Libraries; Link; Longitudinal Studies; Methods; Minor; Modeling; Monoclonal Antibodies; Pattern; Persons; Polymerase; Receptors, Antigen, B-Cell; Specificity; Testing; Vaccine Design; Vaccines; Variant; Viral; Virus; acute infection; adaptive immune response; anti-hepatitis C; chronic infection; cohort; cost; deep sequencing; fitness; genetic approach; in vitro Assay; in vivo; innovation; laboratory experience; neutralizing antibody; novel; pathogen; response; reverse genetics; success; vaccine development; viral fitness; virus envelope; virus host interaction

Project 1: Mechanisms driving breadth of HCV neutralization during repeated control of acute infection in humans PI: Stuart C. Ray, M.D. The primary objective of Project 1 is to study mechanisms driving increased breadth of neutralizing antibody responses during repeated HCV infections that are successfully cleared. We have recently demonstrated that anti-HCV humoral immune responses drive the evolution of HCV proteins E1 and E2 during acute and chronic infection, indicating that neutralizing antibodies detected in our in vitro assays reduce viral fitness in vivo. We have also demonstrated that neutralizing antibodies form clusters of similar specificities by testing them against natural HCV variants that we have cloned in a functional library. We hypothesize that repeated stimulation with varying HCV envelope sequences during reinfection drives broadening of the neutralizing antibody response. Thus, we propose the following aims to elucidate the mechanisms driving HCV neutralization breadth during acute reinfection: (I) to examine dynamic changes in anti-HCV binding and neutralizing activity during HCV re-infection, (II) to determine the mechanistic basis for changes in neutralizing activity by characterizing the circulating B cell repertoire, and (III) to identify key HCV envelope sequence changes that drive broadening of neutralization during reinfection. We anticipate that accomplishing these aims in collaboration with Dr. Cox (project 2) and Dr.Shaw (Project 3) will reveal patterns of antigenic exposure that drive shifts in the B cell response, in a manner that will help guide vaccine design and increase understanding of the host-pathogen interaction.

项目1：在反复控制急性感染过程中驱动HCV中和宽度的机制 在人类中 PI：Stuart C.雷，医学博士 项目1的主要目标是研究驱动中和抗体宽度增加的机制 重复HCV感染期间的反应成功清除。我们最近已经证明， 抗-HCV体液免疫应答在急性和慢性期间驱动HCV蛋白E1和E2的进化 感染，表明在我们的体外测定中检测到的中和抗体降低了体内病毒适应度。我们 也证明了中和抗体通过测试它们可以形成相似特异性的簇 针对我们在功能文库中克隆的天然HCV变体。我们假设重复的 在再感染过程中，不同HCV包膜序列的刺激会扩大中和作用， 抗体反应。因此，我们提出以下目的来阐明驱动HCV的机制 急性再感染期间的中和宽度：（I）检查抗HCV结合的动态变化， HCV再感染期间的中和活性，（II）确定中和活性变化的机制基础 活性通过表征循环B细胞库，和（III）鉴定关键HCV包膜序列 在再感染期间驱动中和作用扩大的变化。我们预计，实现这些目标 与考克斯博士（项目2）和肖博士（项目3）合作的目标将揭示抗原暴露的模式 这将推动B细胞反应的转变，以一种有助于指导疫苗设计和增加 了解宿主-病原体相互作用。