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

基本信息

批准号：
9098152
负责人：
STUART C RAY
金额：
$ 12.23万
依托单位：
JOHNS HOPKINS UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2010
资助国家：
美国
起止时间：
2010-04-15 至 2021-03-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9098152
关键词：
Acute Acute Hepatitis C Affinity Antibody Response Antibody Specificity Automobile Driving B cell repertoire B-Lymphocytes Binding CD4 Positive T Lymphocytes Chronic 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 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 Viral Proteins Virus adaptive immunity anti-hepatitis C base 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

项目摘要

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：在重复控制急性感染期间驱动HCV中和的机制在人类中 PI：Stuart C. Ray，医学博士项目1的主要目的是研究推动抗体中和抗体广度的机制成功清除的重复HCV感染期间的反应。我们最近证明了抗HCV体液免疫反应驱动急性和慢性期间HCV蛋白E1和E2的演变感染，表明在我们的体外测定中检测到的中和抗体可减少体内病毒适应性。我们还表明，中和抗体通过测试形成相似特异性的簇针对我们在功能库中克隆的天然HCV变体。我们假设重复在再感染期间，用不同的HCV包膜序列刺激驱动中和宽阔抗体反应。因此，我们提出以下旨在阐明驱动HCV的机制急性再感染过程中的中和广度：（i）检查抗HCV结合的动态变化和在HCV重新感染期间中和活性，（ii）确定中和变化的机理基础通过表征循环的B细胞库和（iii）来识别关键HCV包膜序列的活动驱动中和拓宽期间中和的变化的变化。我们预计完成这些与Cox博士（项目2）和Shaw博士（项目3）合作的目的将揭示抗原暴露的模式驱动器在B细胞响应中的变化，以有助于指导疫苗设计并增加的方式了解宿主 - 病原体相互作用。