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（由应用程序提供）：HIV特异性中和抗体（NABS）被认为是HIV疫苗反应的关键成分。通过免疫抑制发展有效的NAB反应的主要挑战之一是，我们不知道如何引起此类NAB。在成年人中识别宽阔和潜在的NAB为该领域提供了极大的鼓励，因为它表明可以响应HIV抗原而引起广泛的潜在抗体。但是，迄今为止分离的单元单元主要源自具有长期HIV感染的个体 - 在某些情况下超过十年 - 这些抗体的令人失望的特征是亲和力成熟和与种系的变化的程度，在某些情况下大于40％。尽管这些mAb有助于定义一些受到一些广泛的HIV特异性NAB针对的表位，但它们提出了有关如何通过这些特性引起NABS的挑战问题，因为这些反应在继续多年的HIV序列变化和刺激后不断发展。我们认为，由于免疫可能无法模仿这种长期亲和力成熟过程，因此必须确定是否有可能引起艾滋病毒感染中的快速，广泛的NAB反应，如果是这样，则定义了这种情况的发生。我们最近发现，在某些情况下，在感染的第一年，在某些情况下，感染了艾滋病毒的婴儿在某些情况下会产生广泛而有效的HIV特异性NAB反应。映射研究表明，这些反应与大多数具有广泛NAB活性的成年人的反应不同。我们在这里建议以以下特定目的表征这些新的反应：1）将HIV特异性单克隆抗体与具有广泛NAB的婴儿分离，并定义其反应的宽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mAb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的原始B细胞接收器产生后来的mAb。 4）定义和比较成熟与初始中和抗体的结合特性。开发出快速耐心的HIV特异性NAB反应的婴儿可能会对宽阔和潜在的NAB的性质有重要的线索，这些线索可以通过短期的免疫接种策略引起。我们认为，定义祖细胞受体以及导致这种BNAB的途径和功能相互作用将提供有关如何用真空引起此类反应的关键见解。