THE ROLE OF ANTIBODIES IN MOTHER TO CHILD HIV TRANSMISSION

描述（由申请人提供）：HIV-1继续以惊人的速度传播，在过去几年中，估计每年有400万新感染。目前没有HIV-1候选疫苗对全球流行的各种HIV-1病毒株有效。在实验模型系统中，中和抗体已显示出阻断HIV-1感染。然而，这些结果是在理想条件下获得的，其中使用了被动施用的已知容易中和被测病毒的抗体;大多数HIV-1毒株不会被这些相同的抗体中和。目前，尚不清楚哪种类型的抗体在阻断在高度受影响人群中传播的HIV-1菌株方面最有效。抗体是被动获得的母婴传播的HIV-1的设置，我们最近的研究表明，这些抗体可能会选择逃逸变异的婴儿传播。因此，婴儿暴露于HIV-1从他们的母亲提供了一个设置中检查中和抗体在HIV-1传播中的作用，并表征抗体反应的特异性，可能是保护性的。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，我们建议使用从母乳喂养传播HIV-1的临床试验中收集的库存样本来检验这一假设，该临床试验包括来自肯尼亚内罗毕的425对母婴。在该队列中，定期监测婴儿感染状态，以便明确感染的时间;此外，还可获得各种临床和病毒学数据。使用来自该队列的样本，将针对从感染早期分离的一组HIV-1变异体检查母体中和抗体广度和效力。将在婴儿亚组中对被动转移抗体谱进行类似评价。这些目标的目标是确定与降低HIV-1传播风险相关的中和抗体反应，具体而言，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子。此外，我们建议检查在发生传播的情况下逃避中和抗体的分子基础。这些研究将有助于确定HIV-1包膜蛋白上的关键表位，这些表位有助于HIV-1传播过程中的中和逃逸。总之，这些研究将测试广泛和/或有效的中和抗体反应可以帮助预防HIV-1感染的假设，并且它们可以为能够阻断HIV-1获得的抗体的特异性提供独特的见解。验证这一假设对未来的疫苗设计至关重要，因为它将提供数据来支持或反驳用疫苗免疫原引发中和抗体的重要性。 公共卫生相关性：艾滋病毒疫苗研究的一个主要目标是找到一种方法来引发广泛和有效的中和抗体。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，我们建议测试的假设，广泛和有效的中和抗体保护婴儿的HIV- 1阳性的母亲感染。

DESCRIPTION (provided by applicant): 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. PUBLIC HEALTH RELEVANCE: 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.