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

项目总结/摘要 预先存在的抗体（Ab）应答保护免受感染的能力是现代免疫治疗的范例。 疫苗学其核心思想是抗体具有特定的靶点和赋予保护能力的功能。 一些动物模型和HIV感染者的研究表明，抗体依赖性细胞毒性 （ADCC），其导致被感染细胞的消除，可以防止HIV传播和/或发病， 但总体研究有限。虽然动物模型可以提供对保护机制的深入了解， 通常依赖于单一病毒变体的高挑战剂量，这并不反映天然HIV的设置 传输很少有研究在人类中检查预先存在的ADCC抗体，无论是疫苗引起的还是 被动转移，影响艾滋病毒的传播或发病。在人类研究中， 靶向特定表位的Ab是否对保护至关重要，以及这些表位是否被 ADCC介导的抗体，这是至关重要的信息，利用这些发现的疫苗开发。 由于母体抗体在妊娠后期和妊娠前被动转移到婴儿循环中， 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， 以衡量艾滋病病毒感染和疾病进展之间的相关性。该项目提出， 研究母乳喂养的母婴传播，以便提供更多关于预先存在的 HIV特异性抗体对HIV获得和发病机制的影响。本提案将具体阐述以下假设： 预先存在的和被动转移的母体抗体靶向特异性表位并介导ADCC 保护婴儿免受母婴传播和艾滋病毒致病。在目标1中，母源性ADCC对母婴传播的作用， 随后，将对两个母乳喂养婴儿队列中的艾滋病毒阳性婴儿临床结局进行评估， 先前的工作针对一个新的队列，并使用两种不同的测定来测量血浆ADCC活性。在目标2中， 与MTCT风险相关的血浆靶向HIV表位将使用高通量和高- 分辨率噬菌体展示方法。目标3将侧重于特定的母亲/婴儿对，以分离HIV特异性B细胞 从而更深入地表征HIV特异性和ADCC介导Ab的一个例子， 婴儿的临床结果在两年的随访期内更有利。这些目标将有助于 增加了对抗体特性的了解，这些特性可以抑制HIV的传播和发病机制，从而 提供特征化的终点以改进HIV疫苗和治疗开发。 除了拟议的研究，该奖学金将支持专业发展的 研究人员通过最先进技术的培训，与计算生物学专家合作 和统计，在会议上发言，指导初级科学家，并从事病人护理。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 用于研究和临床培训的网站，这些网站拥有充足的资源，可以完全实现申请目标。

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.