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)：艾滋病毒特异性中和抗体(NAB)被认为是艾滋病毒疫苗反应的关键组成部分。通过免疫制定有效的NAB反应的主要挑战之一是，我们不知道如何引发这种NAB。在成人中发现广泛和有效的NAB为该领域提供了极大的鼓舞，因为这表明可以诱导出广泛和有效的抗体来应对艾滋病毒抗原。然而，迄今为止分离的单抗主要来自长期感染艾滋病毒的人--在某些情况下超过十年--这些抗体的一个令人失望的特征是亲和力成熟和与种系的差异程度，在某些情况下超过40%。因此，虽然这些单抗帮助定义了一些特别广泛的HIV特异性NAB所针对的表位，但它们提出了如何利用这些特性诱导NAB的挑战性问题，因为这些反应是在多年的HIV序列持续变异和刺激后演变而来的。我们认为，由于免疫可能无法模拟这种长期的亲和力成熟过程，因此确定是否有可能在HIV感染中引发快速、广泛的NAB反应是至关重要的，如果可能，则定义这种反应是如何发生的。我们最近发现，感染艾滋病毒的婴儿在感染的第一年内，在某些情况下，会产生广泛而有效的艾滋病毒特异性NAB反应。图谱研究表明，这些反应与大多数具有广泛NAB活性的成年人的反应不同。我们建议用以下特定目的来描述这些新的反应：1)从具有广泛NAB的婴儿中分离出HIV特异性的单抗，并确定其反应的广度是由于多克隆反应还是由于单克隆反应。2)确定影响婴儿反应广度的单抗的表位特异性。3)确定单抗抗体基因的个体发育，确定识别HIV的原始B细胞受体，从而产生新的单抗。4)定义和比较成熟中和抗体与初始中和抗体的结合特性。发展出快速、强大的HIV特异性NAB反应的婴儿可能掌握着广泛和有效的NAB的性质的重要线索，这些NAB可以通过短期免疫策略来引发。我们相信，定义祖细胞B细胞受体以及导致这种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。