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

项目1：在反复控制急性感染期间驱动丙型肝炎病毒中和广度的机制 在人类身上 派：斯图尔特·C·雷，医学博士。 项目1的主要目标是研究中和抗体广度增加的机制 在成功清除的反复丙型肝炎病毒感染期间的反应。我们最近证明了 抗-丙型肝炎病毒体液免疫应答推动急慢性丙型肝炎病毒蛋白E1和E2的演变 感染，表明在我们的体外检测中检测到的中和抗体降低了体内的病毒适合性。我们 还证明了中和抗体通过检测形成了具有类似特异性的簇 针对我们在功能文库中克隆的天然丙型肝炎病毒变异株。我们假设重复一次 在再感染期间用不同的丙型肝炎病毒包膜序列刺激可使中和作用扩大 抗体反应。因此，我们提出以下目的来阐明丙型肝炎病毒的驱动机制 急性再感染期间的中和广度：(I)检测抗-丙型肝炎病毒结合和 丙型肝炎病毒再感染期间的中和活性，(Ii)确定中和变化的机制基础 通过表征循环B细胞库的活性，以及(Iii)识别关键的丙型肝炎病毒包膜序列 在再感染期间推动中和扩大的变化。我们期待着实现这些目标 与考克斯博士(项目2)和肖博士(项目3)合作的AIMS将揭示抗原暴露的模式 这推动了B细胞反应的转变，这将有助于指导疫苗的设计和增加 了解寄主与病原体的相互作用。

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.