Mechanisms of antibody-mediated control of repeated hepatitis C virus infection in humans

项目摘要 广谱中和抗体(BNAbs)体外阻断不同丙型肝炎病毒株的感染，并输注bNAbs 在动物模型中对丙型肝炎病毒感染具有保护作用。与其他一些慢性病毒感染相比，如艾滋病毒- 在bNAb似乎不影响疾病预后的情况下，高血浆bNAb滴度的早期发展是 与人类原发丙型肝炎病毒感染的自发清除有关。尽管很明显，bNAbs 可以在清除原发丙型肝炎病毒感染、详细分析抗体滴度、表位等方面发挥关键作用 与清除感染相关的靶向和B细胞表型仍然缺乏。清白的个人 多重再感染可能是进一步确定保护性抗体反应的理想研究对象。在那些人中 世卫组织清除了他们的第一次感染，80%的人清除了随后的中和抗体(NAB)迅速上升的再次感染 滴度、感染持续时间更短、病毒血症峰值更低，显示出保护性获得性免疫 可以作为理想疫苗反应的模型。目前尚不清楚B细胞应答的哪些参数 对于反复清除感染是最关键的，或者什么抗原刺激是诱导感染所必需的 这些回应。 在本提案的目标1中，我们将定义与血浆抗丙型肝炎病毒抗体结合和中和活性相关的 反复清除再感染。在目标2中，我们将确定改革的机制基础 通过表征循环B细胞库和丙型肝炎病毒之间的动态相互作用来研究中和活性 在再次感染过程中序列发生变化。在目标3中，我们将定义与丙型肝炎病毒相关的特异性B细胞的表型 反复清除再感染。 由于再感染通常被非常有效地清除，这些免疫反应可以作为 应该由疫苗诱导的反应。通过表征血浆抗体反应，B细胞 反复自发性受试者的谱系、病毒抗原变异和B细胞表型 清除感染后，我们将通知丙型肝炎病毒疫苗的开发。

Project Summary Broadly neutralizing antibodies (bNAbs) block infection by diverse HCV strains in vitro, and infusion of bNAbs is protective against HCV infection in animal models. In contrast to some other chronic viral infections like HIV- 1 where bNAbs do not appear to influence disease outcome, early development of high plasma bNAb titers is associated with spontaneous clearance of primary HCV infection in humans. Although it is clear that bNAbs can play a critical role in clearance of primary HCV infection, detailed analysis of antibody titers, epitopes targeted, and B cell phenotypes associated with clearance of infection are still lacking. Individuals who clear multiple reinfections may be the ideal study subjects to further define protective antibody responses. Of those who clear their first infection, 80% clear subsequent reinfections with a rapid rise in neutralizing antibody (NAb) titers, shorter duration of infection, and lower peak viremia, demonstrating protective adaptive immunity that can serve as a model for a desired vaccine response. It is not known which parameters of the B cell response are most critical for repeated clearance of infection, or what antigenic stimuli are necessary for induction of these responses. In Aim 1 of this proposal, we will define plasma anti-HCV antibody binding and neutralizing activity associated with repeated clearance of reinfection. In Aim 2, we will determine the mechanistic basis for changes in neutralizing activity by characterizing the dynamic interplay between the circulating B cell repertoire and HCV sequence changes during reinfection. In Aim 3, we will define phenotypes of HCV-specific B cells associated with repeated clearance of reinfection. Because reinfections are generally cleared very efficiently, these immune responses can serve as a model for responses that should be induced by a vaccine. By characterizing plasma antibody responses, B cell repertoires, viral antigenic variation, and B cell phenotypes in human subjects with repeated spontaneous clearance of infection, we will inform HCV vaccine development.