DEFINING THE INFANT IMMUNE RESPONSE TO HIV

定义婴儿对艾滋病毒的免疫反应

• 批准号: 9076992
• 负责人: JULIE M. OVERBAUGH
• 金额: $ 78.73万
• 依托单位: FRED HUTCHINSON CANCER RESEARCH CENTER
• 依托单位国家: 美国
• 财政年份: 2016
• 资助国家: 美国
• 起止时间: 2016-01-01 至 2020-12-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9076992
• 关键词: AIDS prevention; Address; Adult; Affinity; Amino Acids; Antibodies; Antibody Response; B-Lymphocytes; Binding; Biochemical; Biological Models; Birth; Blood Cells; Breast Feeding; Cells; Clinical Trials; Data; Development; Epitopes; Evolution; Experimental Models; Freezing; Genes; Growth; HIV; HIV Antigens; HIV Infections; HIV vaccine; HIV-1; Immune response; Immunization; Immunoglobulin G; Immunoglobulin Somatic Hypermutation; Individual; Infant; Infection; Life; Maps; Methods; Monoclonal Antibodies; Nature; Pathway interactions; Plasma; Polysaccharides; Positioning Attribute; Process; Property; Receptors, Antigen, B-Cell; Resources; Sampling; Specificity; Time; Vaccines; Variant; Woman; biophysical techniques; cohort; design; innovation; insight; neutralizing antibody; novel; progenitor; public health relevance; response; vaccine response

 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.

 描述（由申请人提供）：HIV 特异性中和抗体 (Nab) 被认为是 HIV 疫苗反应的关键组成部分。通过免疫开发有效的 Nab 反应的主要挑战之一是我们不知道如何引发这种 Nab。在成人中鉴定出广泛且有效的 Nab 为该领域提供了巨大的鼓励，因为它表明可以针对 HIV 抗原引发广泛且有效的抗体。然而，迄今为止分离出的单克隆抗体主要来自长期感染 HIV 的个体（在某些情况下感染超过十年），这些抗体的一个令人失望的特征是亲和力成熟的程度以及与种系的变异程度，在某些情况下大于 40%。因此，虽然这些 Mab 帮助定义了一些特别广泛的 HIV 特异性 Nab 所针对的表位，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，因为这些反应是在多年来持续的 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 反应至关重要，如果可以，则确定其如何发生。我们最近发现，感染 HIV 的婴儿在感染后的第一年内，在某些情况下会产生广泛而有效的 HIV 特异性 Nab 反应。绘图研究表明，这些反应与大多数具有广泛 Nab 活性的成年人中发现的反应不同。我们在此建议通过以下具体目标来表征这些新反应：1）从具有广泛 Nab 的婴儿中分离出 HIV 特异性单克隆抗体，并确定其反应的广度是由于多克隆反应还是单克隆反应。 2) 定义有助于婴儿反应广度的单克隆抗体的表位特异性。 3)确定Mab的抗体基因的个体发育，并定义识别HIV以产生后来的Mab的原始B细胞受体。 4) 定义并比较成熟抗体与初始中和抗体的结合特性。产生快速、强烈的 HIV 特异性 Nab 反应的婴儿可能掌握着通过短期免疫策略引发的广泛而有效的 Nab 性质的重要线索。我们相信，定义祖 B 细胞受体以及产生此类 bNab 的途径和功能相互作用将为如何通过疫苗引发此类反应提供重要见解。