DEFINING THE INFANT IMMUNE RESPONSE TO HIV

 描述（由申请方提供）：HIV特异性中和抗体（Nabs）被认为是HIV疫苗应答的关键组成部分。通过免疫接种制定有效的Nab反应的主要挑战之一是，我们不知道如何引发这样的Nab。在成人中鉴定出广泛而有效的Nab为该领域提供了巨大的鼓励，因为它表明可以在对HIV抗原的反应中引发广泛而有效的抗体。然而，迄今为止分离的单克隆抗体主要来自长期HIV感染的个体-在某些情况下超过十年-并且这些抗体的令人失望的特征是亲和力成熟的程度和来自种系的变异，在某些情况下大于40%。因此，虽然这些单克隆抗体有助于定义一些特别广泛的HIV特异性Nab靶向的表位，但它们提出了关于如何引发具有这些特性的Nab的挑战性问题，因为这些反应是在持续多年的HIV序列变异和刺激后进化的。我们认为，由于免疫可能无法模拟这种类型的长期亲和力成熟过程，因此确定是否有可能在HIV感染中引发快速，广泛的Nab应答至关重要，如果是这样，则定义这是如何发生的。我们最近发现，感染艾滋病毒的婴儿在感染后的第一年内就会产生广泛而有效的艾滋病毒特异性Nab反应。映射研究表明，这些反应是不同的，在大多数成年人广泛的Nab活动。我们在此建议用以下特异性AIM来表征这些新的应答：1）从具有广泛Nab的婴儿中分离HIV特异性单克隆抗体，并确定其应答的广度是由于多克隆应答还是单克隆应答。2)确定单克隆抗体的表位特异性，其有助于婴儿应答的广度。3)确定MaB抗体基因的个体发生，并确定识别HIV的原始B细胞受体，以产生后来的MaB。4)定义并比较成熟中和抗体与初始中和抗体的结合特性。婴儿谁制定了一个快速强大的艾滋病毒特异性Nab反应可能持有的广泛和有效的Nab的性质，可以引发与短期免疫策略的重要线索。我们相信，确定祖B细胞受体和导致这种bNab的途径和功能相互作用将为如何用疫苗引发这种反应提供关键的见解。

 DESCRIPTION (provided by applicant): HIV-specific neutralizing antibodies (Nabs) are considered a critical component of a HIV vaccine response. One of the major challenges to developing an effective Nab response through immunization is that we do not know how to elicit such Nabs. The identification of broad and potent Nabs in adults provided great encouragement for the field, as it suggested that broad and potent antibodies can be elicited in response to HIV antigens. However, the Mabs isolated to date are largely derived from individuals with a long-term HIV infection - in some cases greater than a decade - and a disappointing feature of these antibodies is the extent of affinity maturation and variation from germline, which is greater than 40% in some cases. Thus, while these Mabs helped define epitopes targeted by some notably broad HIV-specific Nabs, they raise challenging issues regarding how to elicit Nabs with these properties, as these responses have evolved after continued HIV sequence variation and stimulation over many years. We believe that because immunization may not be able to mimic this type of long-term affinity maturation process, it is critical to determine if it is possible t elicit a rapid, broad Nab response in HIV infection, and if so, to define how this occurs. We recently discovered that HIV-infected infants develop broad and potent HIV-specific Nab responses, in some cases, within the first year of their infection. Mapping studies suggest that these responses are distinct from those found in most adults with broad Nab activity. We propose here to characterize these novel responses with the following specific AIMs: 1) To isolate HIV-specific monoclonal antibodies from infants with broad Nabs and define whether the breadth of their response is due to a polyclonal response or a monoclonal response. 2) To define the epitope specificity of the Mabs that contributed to the breadth of the infant response. 3) To determine the ontogeny of the antibody gene of the Mab and define the original B cell receptor that recognized HIV to give rise to the later Mab. 4) To define and compare the binding properties of mature versus initial neutralizing antibodies. Infants who developed a rapid robust HIV-specific Nab response may hold important clues to the nature of broad and potent Nabs that can be elicited with shorter-term immunization strategies. We believe that defining the progenitor B cell receptor and the pathway and functional interactions that resulted in such bNabs will provide critical insights into how to elicit such responses with a vaccine.