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，但缺乏数据表明这种抗体在艾滋病毒暴露人群中提供保护的潜力。对HIV的保护性抗体反应必须包括表现出足够广度的抗体，以识别不同的HIV-1循环菌株，这些菌株在包膜序列上可能有30%的差异。因此，虽然在猕猴模型系统中的研究表明，抗体可以提供对单一变种的保护，但这些模型不能解决抗体对流行的艾滋病毒毒株的压倒性抗原多样性的保护潜力。在母婴传播(MTCT)的环境中，包括母乳传播，母亲和婴儿中都存在抗体压力，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的模型，说明了疫苗诱导艾滋病毒特异性抗体可能发生的情况，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因素。中和抗体和通过抗体依赖的细胞毒性(ADCC)发挥作用的抗体现在都被认为在MTCT环境中具有保护作用，两者都可以发挥作用。然而，母婴HIV抗体与传播有关的研究结果各不相同，阻碍了我们对母婴传播免疫相关性的清楚了解。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/或使用了与传播发生的时间相关的次优时间点的样本。在这里，我们将利用MTCT的一项大型临床试验--内罗毕母乳喂养临床试验--该试验招募了数百名艾滋病毒阳性孕妇，并对她们从怀孕晚期到婴儿两年的生命进行了跟踪。在这项试验中，母亲和婴儿都进行了定期的随访，并从这项研究中获得了丰富的数据和银行样本。在这里，我们建议利用这一独特的大型队列，定期收集样本和详细的婴儿感染数据，以检查母婴ADCC在母婴传播中的作用。我们还将研究抗体反应，包括结合和中和抗体及其表位特异性，与婴儿感染艾滋病毒的关系。总而言之，这些研究将在一个描述良好的MTCT抗体相关性队列中提供全面的数据。这些信息对于确定在MTCT环境中提供保护的抗体的功能和特异性至关重要，这反过来将为开发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.