Studying the Contribution of Env-SpecificAntibodies to Mother to Child Transmission of HIV-1

项目摘要/摘要 预先存在的抗体(Ab)反应预防感染的能力是现代 疫苗学。这一点的核心是，抗体具有特定的目标和功能，可以赋予保护能力。 一些动物模型和对HIV感染者的研究表明，抗体依赖的细胞毒性 (ADCC)可以消除受感染的细胞，可以防止艾滋病毒传播和/或致病， 但总体来说，研究是有限的。尽管动物模型可以提供对保护机制的洞察，但它们 通常依赖于单一病毒变异的高挑战剂量，这不能反映自然艾滋病毒的环境 变速箱。很少有研究在人类身上检验预先存在的ADCC抗体，无论是疫苗引发的还是 被动传播，影响艾滋病毒的传播或致病。在人类研究中也有不同的关于 靶向特定表位的抗体是否对保护至关重要，以及这些表位是否被 ADCC-介导抗体，这是利用这些发现进行疫苗开发的关键信息。 由于母体抗体在怀孕后期和怀孕前被动地转移到婴儿的循环中 母乳喂养暴露于艾滋病毒，母婴传播(MTCT)是一种罕见的自然环境，在这种情况下 以衡量预防艾滋病毒感染和疾病进展的相关性。该项目提出了 研究母乳喂养母婴传播，以提供更相关的人类数据，了解预先存在的和 HIV特异性抗体对HIV感染及致病机制的影响。这项提议将具体解决以下假设 针对特定表位的预先存在和被动转移的母源抗体及其介导的ADCC 保护婴儿免受母婴传播和艾滋病毒的感染。在目标1中，母源ADCC在母体母体感染和母体感染中的作用 随后将评估两组母乳喂养婴儿中HIV+婴儿的临床结果，扩大范围 之前的工作是在一个新的队列中进行，并使用两种不同的方法来测量血浆ADCC的活性。在目标2中， 与母婴传播风险相关的血浆靶向HIV表位将使用高通量和高通量 分辨率噬菌体展示法。目标3将重点放在分离HIV特异性B细胞的特定母婴对上 从而更深入地表征了HIV特异性和ADCC介导型抗体的一个例子 在两年的随访期内，婴儿的临床结果更有利。这些目标加在一起，将有助于 增加对抗体特性的理解，从而抑制艾滋病毒的传播和发病 提供有特色的终点，以改进艾滋病毒疫苗和治疗开发。 除了建议的研究外，这项奖学金还将支持 通过最新技术培训的研究人员，与计算生物学专家合作 和统计，在会议上发表演讲，指导初级科学家，并参与病人护理。所有活动 将在弗雷德·哈钦森癌症研究中心和华盛顿大学举行，这两个世界著名的 研究和临床培训网站，这些网站有充足的资源来完全实现应用目标。

PROJECT SUMMARY/ABSTRACT The capacity of pre-existing antibody (Ab) responses to protect from infection is a paradigm of modern vaccinology. Central to this is the idea that Abs have specific targets and functions that impart protective capacity. Some animal models and studies of HIV-infected individuals suggest that antibody dependent cellular cytotoxicity (ADCC), which leads to elimination of infected cells, may protect against HIV transmission and/or pathogenesis, but studies are limited overall. Although animal models can provide insight into mechanisms of protection, they often rely upon high challenge doses of a single viral variant, which does not reflect the setting of natural HIV transmission. Few studies have examined in humans whether pre-existing ADCC Abs, either vaccine-elicited or passively-transferred, influence HIV transmission or pathogenesis. There is also variation in human studies on whether Abs targeting specific epitopes are critical for protection and whether such epitopes are recognized by ADCC-mediating Abs, information which is critical to harnessing these findings for vaccine development. As maternal Abs are passively transferred to the infant circulation late in pregnancy and before breastfeeding exposure to HIV, mother to child transmission (MTCT) represents a rare, natural setting in which to gauge the correlates of protection against HIV acquisition and disease progression. This project proposes to study breastfeeding MTCT in order to provide more relevant human data on the influence of pre-existing and HIV-specific Abs on HIV acquisition and pathogenesis. This proposal will specifically address the hypothesis that pre-existing and passively-transferred maternal antibodies targeting specific epitopes and that mediate ADCC protect infants from MTCT and HIV pathogenesis. In Aim 1, the role of maternally-derived ADCC on MTCT and subsequent HIV+ infant clinical outcome among two cohorts of breastfeeding infants will be evaluated, expanding previous work to a novel cohort and using two distinct assays to measure plasma ADCC activity. In Aim 2, the plasma targeted HIV epitopes associated with MTCT risk will be identified using a high-throughput and high- resolution phage-display approach. Aim 3 will focus on a specific mother/infant pair to isolate HIV-specific B cells and thereby more deeply characterize one example of HIV-specific and ADCC-mediating Abs in a setting where infant clinical outcome was more favorable over a two-year follow-up period. Together, these aims will contribute to an increased understanding of the Ab properties that can curb HIV transmission and pathogenesis, thereby providing characterized end-points to improve HIV vaccine and therapeutic development. In addition to the proposed research, this fellowship will support the professional development of the investigator through training in state-of-the-art techniques, collaborating with experts in computational biology and statistics, presenting at conferences, mentoring junior scientists, and engaging in patient care. All activities will take place at Fred Hutchinson Cancer Research Center and University of Washington, two world-renowned sites for research and clinical training, which have ample resources to completely fulfill the application goals.