THE ROLE OF ANTIBODIES IN MOTHER TO CHILD HIV TRANSMISSION

描述：艾滋病毒特异性抗体被认为是艾滋病毒疫苗反应的关键组成部分，但缺乏证明此类抗体在艾滋病毒暴露人群中提供保护的潜力的数据。对HIV的保护性抗体应答必须包括具有足够广度的抗体，以识别不同的HIV-1循环染色，其包膜序列可能相差30%。因此，尽管在猕猴模型系统中的研究表明，抗体可以提供针对单一变体的保护，但这些模型无法解决抗体保护针对循环HIV毒株压倒性抗原多样性的潜力。在母婴传播（MTCT）的情况下，包括母乳喂养传播，母亲和婴儿都存在抗体压力，因此有可能通过多种机制影响传播。因此，婴儿接触艾滋病毒提供了一个自然模型，说明使用诱导艾滋病毒特异性抗体的疫苗可能会发生什么，并提供了一个独特的机会来确定预防艾滋病毒感染的体液免疫相关关系。中和抗体和通过抗体依赖性细胞毒性（ADCC）起作用的抗体现在都与MTCT的保护作用有关，两者都可能发挥作用。然而，母婴艾滋病毒抗体与传播相关的研究结果不一，阻碍了我们清晰了解母婴间母婴传播中免疫相关因素的能力。这些差异很可能反映了这样一个事实，即许多研究规模较小和/或使用的样本来自与传播发生时间相关的次优时间点。在这里，我们将利用一项大规模的母婴传播临床试验——内罗毕母乳喂养临床试验——招募了数百名艾滋病毒阳性孕妇，从妊娠晚期到婴儿两岁。在这项试验中，对母亲和婴儿进行了定期随访，并从这项研究中获得了丰富的数据和储存的样本。在这里，我们建议利用这个独特的大队列，定期收集样本和详细的婴儿感染数据，来检查母婴ADCC在MTCT中的作用。我们还将研究抗体反应的关系，包括结合和中和抗体及其表位特异性，与婴儿艾滋病毒获得。总之，这些研究将在一个具有良好特征的MTCT抗体相关队列中提供全面的数据。这些信息对于确定在MTCT情况下提供保护的抗体的功能和特异性至关重要，这反过来又将为制定有效的疫苗战略提供信息。

DESCRIPTION: HIV-specific antibodies are considered a critical component of a HIV vaccine response, yet there is a paucity of data demonstrating the potential of such antibodies to provide protection in HIV exposed populations. A protective antibody response to HIV must include antibodies that exhibit adequate breadth to recognize diverse circulating stains of HIV-1, which can differ by 30% in envelope sequence. Thus, while studies in macaque model systems demonstrate that antibodies can provide protection against a single variant, these models cannot address the potential of antibodies to protect against the overwhelming antigenic diversity of circulating HIV strains. In the setting of mother-to-child transmission (MTCT), including breastfeeding transmission, antibody pressure is present in both the mother and the infant and thus has the potential to impact transmission by multiple mechanisms. Therefore, infant HIV exposure provides a natural model of what might occur with a vaccine that induced HIV-specific antibodies, and a unique opportunity to define humoral immune correlates of protection against HIV infection. Both neutralizing antibodies and antibodies that act through antibody-dependent cell cytoxicity (ADCC) have now been implicated in protection in the setting of MTCT and both could play a role. However, variable results across studies of maternal and infant HIV antibodies in relation to transmission has hindered our ability to gain a clear picture f immune correlates in MTCT. These discrepancies most likely reflect the fact that many studies were small and/or used samples from suboptimal time points in relation to when transmission occurred. Here we will capitalize on a large clinical trial of MTCT - the Nairobi Breastfeeding Clinical Trial - that enrolled several hundred HIV positive pregnant women and followed them from the third trimester through 2 years of life in the infant. In this trial, there was regular folow-up of both mothers and infants and there is a wealth of data from this study as well as banked samples. Here we propose to utilize this unique large cohort with regular sample collection and detailed data on infant infection to examine the role of both maternal and infant ADCC in MTCT. We will also examine the relationship of antibody responses, including binding and neutralizing antibodies and their epitope specificity, with infant HIV acquisition. Together these studies will provide comprehensive data within one well-characterized cohort on antibody correlates of MTCT. Such information is critical to determining the function and specificity of antibodies that provide protection in the setting of MTCT, which in turn will inform developing effective vaccine strategies.