The role of antibodies in mother to child HIV transmission

摘要： 为了利用艾滋病毒特异性抗体反应的潜力进行预防，重要的是定义 阻断HIV感染或减缓疾病的抗体类型。动物模型经常被用作研究的第一步 定义原则证明概念和在非人类灵长类动物艾滋病毒模型中进行的许多优雅研究支持 抗体有可能提供免受感染和疾病的保护。然而，从这些方面来看， 研究是在非常受控的情况下进行的，使用单一病毒株，以了解 在更为复杂的自然艾滋病毒感染背景下，免疫保护机制具有挑战性。它是 只有在有HIV感染者的情况下才有可能研究人类的免疫相关性 携带HIV特异性抗体的人，其中一部分人没有感染，而另一些人则屈服了。这发生在设置中 艾滋病毒的母婴传播，特别是产后感染，其中母亲抗体是 传给婴儿，并在出生时达到最高水平。因此，母婴传播是为数不多的案例之一。 在那里可以研究针对艾滋病毒的保护性抗体的特征。我们的团队有几个杰出的 队列研究使我们能够在母婴传播中确定免疫相关性。我们在上一笔助学金中的研究 Cycle显示非中和抗体与抗体依赖的细胞细胞毒作用之间存在关联 (ADCC)和婴儿结局。这些研究是第一批表明ADCC抗体在 对接触者的保护，并支持RV144艾滋病毒疫苗试验的结果。在这里，我们建议在此基础上 这些发现更准确地定义了ADCC抗体的靶点和功能，与更好的 使用一系列创新方法的婴儿结局，包括系统血清学和新的噬菌体展示 方法。我们将进一步探索ADCC活动的性质，使用不同方法测量ADCC 方式。我们将从高传染性的非传播母亲中分离出ADCC抗体，以开始确定细节 保护性抗体的功能特性及其来源。因为人体研究要比 与实验研究相比，复杂且容易受到混淆的影响，确定是否相同 在不同的队列中确定相关性是至关重要的。因此，这笔赠款旨在采取广泛的方法来 在第一个队列研究中确定保护的相关性，然后在第二个队列研究中测试已识别的相关性 队列研究。总体而言，拟议的研究将利用独特的队列和来自先前拨款的令人兴奋的发现 提供对有助于预防艾滋病毒感染的抗体的特征的关键洞察 在人类身上。

ABSTRACT: In order to harness the potential of the HIV-specific antibody response for prevention, it is important to define the types of antibodies that block HIV infection or slow disease. Animal models are often used as a first step in defining proof-of-principle concepts and many elegant studies in non-human primate models of HIV support the potential of antibodies to provide protection from infection and disease. However, moving forward from these studies, which are conducted under very controlled situations and with a single viral strain, to understanding immune mechanisms of protection in the much more complex setting of natural HIV infection is challenging. It is really only possible to study immune correlates in humans in situations where there are HIV-exposed individuals who carry HIV-specific Abs where a subset remains uninfected while others succumb. This occurs in the setting of mother-to-child transmission (MTCT) of HIV, particularly postpartum infection, where maternal antibodies are passed to the infant and achieve their highest levels at birth. Thus, MTCT represents one of the few cases where the characteristics of protective antibodies can be studied for HIV. Our team has several remarkable cohort studies that uniquely position us to define immune correlates in MTCT. Our studies in the previous grant cycle showed an association between non-neutralizing Abs capable of antibody-dependent cellular cytotoxicity (ADCC) and infant outcomes. These studies represent one of the first to suggest a role for ADCC antibodies in protection in exposed humans and support findings of the RV144 HIV vaccine trial. Here we propose to build on these findings to more precisely define the target and function of the ADCC antibodies associated with better infant outcomes using an array of innovative methods, including systems serology and a new phage display method. We will further explore the nature of the ADCC activity using assays that measure ADCC in different ways. We will isolate ADCC antibodies from highly infectious non-transmitting mothers to begin to define details of the functional properties of protective antibodies and their origin. Because human studies are much more complex and subject to confounding influences compared to experimental studies, determining if the same correlates are identified in different cohorts is critical. Thus, this grant is design to take a broad approach to defining correlates of protection in a first cohort study followed by testing of identified correlates in a second cohort study. Overall, the proposed studies will leverage unique cohorts and exciting findings from the prior grant cycle to provide critical insight into the characteristics of antibodies that contribute to protection from HIV-infection in humans.