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（NABS）被认为是发展有效的NAB响应的主要挑战的关键组成部分，我们不知道某些人知道现在可以识别成人伟大的广泛而有效的NABS对该领域的鼓励是对艾滋病毒抗原的反应。因此，在某些情况下，它大于40％，而MAB在继续使用HIV序列变化和刺激后，以某些较广泛的HIV特异性nabs靶向。长期亲和力成熟的类型是如何发生这种情况的。我们在这里提出以下特定目的来表征这些反应：1）将HIV特异性的单克隆抗体与宽阔的NAVS分离出来，并定义复位的广度是由于呼吸或单克隆反应而定对婴儿呼吸的广度的表位特异性。与最初的中和抗体相对于较短的HIV特异性NAB反应的婴儿可能会使用较短洞悉如何到达到达与疫苗相处。