THE ROLE OF ANTIBODIES IN MOTHER TO CHILD HIV TRANSMISSION

项目摘要 HIV-1继续以惊人的速度蔓延，每年估计有400万新感染病例， 过去的几年里目前还没有HIV-1候选疫苗证明对 在全球范围内传播的各种HIV-1病毒株。中和抗体可以阻断 实验模型系统中的HIV-1感染。然而，这些结果是在理想条件下获得的。 条件，其中被动施用已知容易中和病毒的抗体， 大多数HIV-1病毒株不会被这些相同的抗体中和。目前是 目前还不清楚哪种抗体对阻断正在传播的HIV-1病毒株最有效 在高度受影响的人群中。抗体是在母婴传播HIV-1的情况下被动获得的 传播，我们最近的研究表明，这些抗体可能选择逃避传播， 变种宝宝因此，婴儿从母亲那里接触HIV-1提供了一种环境， 研究中和抗体在HIV-1传播中的作用，并描述 可能具有保护作用的抗体反应。我们假设有中和抗体 有助于保护婴儿免受HIV-1感染。在这里，我们建议使用以下方法来验证这一假设： 从母乳喂养传播HIV-1的临床试验中收集的库存样本，其中包括425 来自肯尼亚内罗毕的母婴对。在该队列中，定期监测婴儿感染状况， 间隔，以便感染的时间是明确的;此外，各种临床和病毒学数据， available.使用来自该队列的样本，将评估母体中和抗体的广度和效力。 对一组从感染早期分离的HIV-1变异体进行了检查。被动转移抗体 将在婴儿的子集中类似地评估分布。这些目标的目标是确定 中和抗体应答与HIV-1传播风险降低相关，具体而言， 对特定病毒株的效力、广度或特异性是否是传播风险的最佳预测因素。 此外，我们还建议研究在某些情况下逃避中和抗体的分子基础。 发生传播的地方。这些研究将有助于确定HIV-1包膜上的关键表位 在HIV-1传播过程中有助于中和逃逸的蛋白质。这些研究将共同测试 广泛和/或有效的中和抗体反应可以帮助预防HIV-1的假设 感染，他们可能提供独特的见解抗体的特异性，能够阻断感染， HIV-1感染。验证这一假设对未来的疫苗设计至关重要，因为它将 提供数据支持或反驳疫苗引发中和抗体的重要性 免疫原项目叙述 艾滋病毒疫苗研究的一个主要目标是找到一种引发广泛且有效的中和抗体的方法。 然而，没有直接证据表明这种抗体实际上可以保护人类免受HIV-1感染。 在这里，我们建议测试广泛而有效的中和抗体保护HIV婴儿的假设- 1例阳性母亲感染。

PROJECT SUMMARY HIV-1 continues to spread at an alarming rate, with an estimated 4 million new infections occurring each of the last several years. There are currently no HIV-1 vaccine candidates that demonstrate efficacy against the diverse HIV-1 strains that are circulating globally. Neutralizing antibodies have been shown to block HIV-1 infection in experimental model systems. However, these results were obtained under ideal conditions, where passively administered antibodies that were known to readily neutralize the virus being tested were used; most HIV-1 strains would not be neutralized by these same antibodies. At present, it is unclear what types of antibodies would be most effective in blocking the strains of HIV-1 that are circulating in highly affected populations. Antibodies are passively acquired in the setting of mother-to-child HIV-1 transmission, and our recent studies suggest that these antibodies may select for transmission of escape variants to the infant. Thus, the exposure of infants to HIV-1 from their mother provides a setting in which to examine the role of neutralizing antibodies in HIV-1 transmission, and to characterize the specificity of antibody responses that may be protective. We hypothesize that there are neutralizing antibodies that contribute to protection of the infant from HIV-1 infection. Here, we propose to test this hypothesis using banked samples collected from a clinical trial of breastfeeding transmission of HIV-1 that included 425 mother-infant pairs from Nairobi, Kenya. In this cohort, infant infection status was monitored at regular intervals, so that the timing of infection is well defined; In addition a variety of clinical and virological data is available. Using samples from this cohort, maternal neutralizing antibody breadth and potency will be examined against a panel of HIV-1 variants isolated from early in infection. Passively transferred antibody profiles will be similarly evaluated in a subset of infants. The goal of these aims will be to identify the neutralizing antibody responses that correlate with a reduced risk of HIV-1 transmission, and specifically, whether potency, breadth or specificity for particular viral strains is the best predictor of transmission risk. In addition, we propose to examine the molecular basis for escape from neutralizing antibodies in cases where transmission has occurred. These studies will help define critical epitopes on the HIV-1 envelope protein that contribute to neutralization escape during HIV-1 transmission. Together, these studies will test the hypothesis that broad and/or potent neutralizing antibody responses can help protect against HIV-1 infection, and they may provide unique insights into the specificity of antibodies that are capable of blocking HIV-1 acquisition. Testing this hypothesis is of critical importance to future vaccine design, because it will provide data to support or refute the importance of eliciting neutralizing antibodies with a vaccine immunogen. PROJECT NARRATIVE A major goal of HIV vaccine research is to find a means to elicit broad and potent neutralizing antibodies. However, there is no direct evidence that such antibodies actually protect humans from HIV-1 infection. Here, we propose to test the hypothesis that broad and potent neutralizing antibodies protect infants of HIV- 1 positive mothers from infection.