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

• 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
• 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' 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

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，HIV-1 疫苗研究的主要目标。在过去的十年里， 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： 免疫接种。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 已知的抗体在动物研究中显示出令人印象深刻的保护潜力。然而，发展 通过免疫接种 VRC01 级 bNAb 需要克服几个障碍。一个成功的 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，最大限度地减少 BNAb 的扩张 竞争脱靶 B 细胞，开发最佳“增强”Env 免疫原以指导适当的 抗体成熟，以及持续 T 辅助反应的供应。在这里我们建议测试概念，而不是 之前经过测试，我们开发了该方法来直接解决这些问题。我们将评估一项新策略 基于我们针对种系 VRC01 生成的抗独特型单克隆抗体 (aiMAb) BCR 类。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 并进一步扩展环境免疫。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 加强免疫期间的超突变。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。我们将测试我们的提议 通过迭代方法和良好集成的实验来制定策略。我们提供的初步数据支持 我们的总体方法。