The role of antibodies in mother to child HIV transmission

摘要： 为了利用HIV特异性抗体反应的潜力进行预防，重要的是确定 阻止艾滋病毒感染或减缓疾病的抗体类型。动物模型通常被用作研究的第一步。 定义原理证明概念和许多在非人类灵长类动物HIV模型中的优雅研究支持 抗体提供保护免受感染和疾病的潜力。但是，从这些 研究，这是在非常受控的情况下进行，并与单一的病毒株，以了解 在更复杂的自然HIV感染环境中的免疫保护机制具有挑战性。是 只有在有艾滋病病毒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，其中一部分人未被感染，而另一部分人则死亡。这发生在设置 艾滋病毒母婴传播（MTCT），特别是产后感染，母体抗体 传递给婴儿，并在出生时达到最高水平。因此，母婴传播是为数不多的 在那里可以研究HIV的保护性抗体的特性。我们的团队有几个非凡的 队列研究使我们能够确定MTCT中的免疫相关性。我们在上一次资助中的研究 循环显示能够产生抗体依赖性细胞毒性的非中和抗体之间的关联 （ADCC）和婴儿结局。这些研究代表了最早提出ADCC抗体在 保护暴露的人，并支持RV144艾滋病毒疫苗试验的结果。在这里，我们建议建立在 这些发现可以更精确地定义ADCC抗体的靶点和功能， 使用一系列创新方法，包括系统血清学和新的噬菌体展示， 法我们将进一步探索ADCC活性的性质，使用测定ADCC在不同的细胞中的活性的方法。 的方式我们将从高传染性的非传播母亲中分离ADCC抗体，开始确定细节 保护性抗体的功能特性及其来源。因为对人类的研究 与实验研究相比，复杂且易受混杂影响，确定是否相同 在不同的队列中识别相关性是至关重要的。因此，这笔赠款旨在采取广泛的方法， 在第一组群研究中定义保护的相关性，然后在第二组群研究中测试鉴定的相关性， 队列研究总的来说，拟议的研究将利用独特的队列和令人兴奋的发现，从以前的赠款 循环，以提供关键的洞察抗体的特点，有助于保护免受艾滋病毒感染 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.