Expansion and targeted maturation of germline HIV-1 bNAb-associated BCRs

种系 HIV-1 bNAb 相关 BCR 的扩增和靶向成熟

基本信息

批准号：
10300438
负责人：
Leonidas Stamatatos
金额：
$ 58.66万
依托单位：
FRED HUTCHINSON CANCER RESEARCH CENTER
依托单位国家：
美国
项目类别：
财政年份：
2018
资助国家：
美国
起止时间：
2018-12-06 至 2022-03-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10300438
关键词：
AIDS/HIV problem Address Affinity Animal Model Animals Anti-Idiotypic Antibodies Antibodies Antibody Response Antigens B-Cell Antigen Receptor B-Cell Development B-Lymphocytes Binding Bypass Clone Cells Communication Data Development Engineering Epidemic Fred Hutchinson Cancer Research Center Frequencies Genes Goals Grant Growth HIV-1 HIV-1 vaccine Human Immune system Immunization Immunoglobulin Somatic Hypermutation Immunology Infection Institution Link Mind Monoclonal Antibodies Mutate National Institute of Allergy and Infectious Disease Participant Pathway interactions Polysaccharides Probability Process Reaction Reagent Receptor Cell Scheme Secondary Immunization Site Sjogren&apos s Syndrome Structure of germinal center of lymph node Testing Universities Vaccination Vaccine Research base design experimental study glycosylation humanized mouse improved in vivo neutralizing antibody nonhuman primate novel passive antibodies prevent programs recruit response structural biology vaccination strategy

项目摘要

ABSTRACT The elicitation of potent and broad HIV-1 neutralizing antibodies (bNAbs) by immunization has been one of the major goals of HIV-1 vaccine research since the beginning of the HIV/AIDS epidemic. During the past decade, significant technical and conceptual advances have enabled the isolation and detailed characterization of a plethora of new bNAbs from HIV-1-infected subjects. The structural characterization of such antibodies, combined with information on their ontogenies, has vastly improved our understanding of how such antibodies are generated during natural infection, leading to new hypotheses regarding how to elicit them by immunization. Our HIVRAD Program grant aims at testing novel reagents and prime-boost immunization schemes to elicit VRC01-class bNAbs, which are among the most broad and potent HIV-1 neutralizing antibodies known and display impressive protective potential in animal studies. However, the development of VRC01-class bNAbs by immunization will necessitate overcoming several obstacles. A successful immunization scheme will likely require, at a minimum, the availability of novel immunogens to initiate and guide the bNAb maturation process, the development of strategies that will minimize the expansion of competing off-target B cells, the development of optimal ‘boost’ Env immunogens to guide the appropriate antibody maturation, and the supply of sustained T helper responses. Here we propose to test concepts, not tested previously, that we have developed to directly address these issues. One new strategy we will evaluate is based on the use of anti-idiotypic monoclonal antibodies (aiMAbs) we generated against germline VRC01- class BCRs. Our preliminary data suggest that these aiMAbs specifically expand naive B cells that express germline VRC01-class B cell receptors (BCRs) and that these cells enter the germinal center (GC) reaction and expand even further upon Env immunization. One obvious advantage is a greater expansion in GC of desired B cells over ‘off target’ B cells, thus improving our chance to induce the correct set of somatic hypermutations during the boost immunizations. Thus, immunizations with aiMAbs will be followed by booster immunizations with an Env specifically designed to engage germline VRC01-class BCRs (426c Core) and then with Envs expressing key steric blocks for VRC01-class antibodies. In this regard we highlight the fact that since our initial submission we generated new information which indicates that the 426c Core elicits antibodies that bypass glycans on the conserved N-linked glycosylation site N276, which are one of the major obstacles preventing germline VRC01-class antibodies from becoming broadly neutralizing. We will test our proposed strategy by an iterative approach with well-integrated experiments. The preliminary data we present support our overall approach.

抽象的通过免疫接种产生有效且广泛的 HIV-1 中和抗体 (bNAb) 一直是解决这一问题的方法之一。自艾滋病毒/艾滋病流行以来，艾滋病毒-1疫苗研究的主要目标是：重大的技术和概念进步使得能够隔离和详细表征来自 HIV-1 感染受试者的大量新 bNAb 此类抗体的结构特征，结合其个体发育信息，极大地提高了我们对此类抗体如何发挥作用的理解是在自然感染过程中产生的，导致了关于如何通过以下方式引发它们的新假设：我们的 HIVRAD 计划赠款旨在测试新型试剂和初免-加强免疫。引发 VRC01 类 bNAb 的计划，这是最广泛、最有效的 HIV-1 中和药物之一已知抗体并在动物研究中显示出令人印象深刻的保护潜力。 VRC01 级 bNAb 的免疫接种需要克服几个障碍才能获得成功。免疫计划可能至少需要有新的免疫原来启动和指导 bNAb 成熟过程，制定策略以最大限度地减少 BNAb 的扩张竞争脱靶最佳 B 细胞，开发“增强”Env 免疫原来指导适当的抗体成熟和持续 T 辅助反应的提供在这里我们建议测试概念，而不是测试概念。之前经过测试，我们开发了一项直接解决这些问题的新策略，我们将对其进行评估。基于我们针对种系 VRC01 生成的抗独特型单克隆抗体 (aiMAb) 我们的初步数据表明，这些 aiMAb 特异性扩增表达的幼稚 B 细胞。种系 VRC01 类 B 细胞受体 (BCR) 以及这些细胞进入生发中心 (GC) 反应并进一步扩展 Env 免疫，一个明显的优势是 GC 的更大扩展。所需的 B 细胞超过“脱靶”B 细胞，从而提高我们诱导正确的体细胞集的机会因此，使用 aiMAb 免疫后将进行加强免疫。使用专门设计用于接合种系 VRC01 级 BCR（426c 核心）的 Env 进行免疫接种，然后 Envs 表达 VRC01 类抗体的关键空间块在这方面，我们强调以下事实：自我们首次提交以来，我们生成了新信息，表明 426c Core 会引发抗体绕过保守的 N 连接糖基化位点 N276 上的聚糖，这是主要障碍之一防止种系 VRC01 类抗体变得广泛中和我们将测试我们提出的建议。我们提供的初步数据支持通过迭代方法和良好集成的实验来制定策略。我们的总体方法。