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: 10593443
• 负责人: Leonidas Stamatatos
• 金额: $ 130.34万
• 依托单位: FRED HUTCHINSON CANCER 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 2023-11-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10593443
• 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 通过免疫引起的潜力和广泛的HIV-1中和抗体（BNAB）一直是其中之一 自HIV/AIDS流行病开始以来，HIV-1疫苗研究的主要目标。在过去的十年中， 显着的技术和概念进步使一个孤立和详细的表征 来自HIV-1感染受试者的大量新BNAB。这种抗体的结构表征， 结合有关其本基因的信息，大大改善了我们对这种抗体的理解 是在自然感染期间产生的，导致有关如何通过 我们的HIVRAD计划赠款旨在测试新型试剂和原始促进免疫 引发VRC01级BNAB的方案，这是最广泛和潜在的HIV-1中和 在动物研究中已知并显示出令人印象深刻的保护潜力。但是，发展 通过免疫接种将有必要克服几个障碍。成功 免疫化方案可能至少需要新颖的免疫原子的可用性来启动和 指导BNAB成熟过程，制定将最大程度地扩展的策略 竞争脱离目标B细胞，最佳的“增强” Env疫苗的发展以指导适当的 抗体成熟和持续T辅助反应的供应。在这里，我们建议测试概念，而不是 先前测试过，我们已经开发出来直接解决这些问题。我们将评估的一种新策略 基于我们针对种系VRC01-产生的抗IDiotypic单克隆抗体（AIMAB）的使用 BCR类。我们的初步数据表明，这些AIMAB专门扩展了表达的天真B细胞 种系VRC01级B细胞受体（BCR），这些细胞进入生发中心（GC）反应 并在免疫抑制后进一步扩展。一个明显的优势是GC的扩展更大 所需的B单元在“ off Target” B细胞上，从而提高了我们诱导正确的体细胞的机会 增强免疫接种期间的高压。那就是，助推器将随后使用AIMAB进行免疫接种 具有专门设计的ENV的免疫接种，以吸引种系VRC01级BCR（426C核心），然后 用ENV表示VRC01类抗体的关键空间块。在这方面，我们强调了一个事实 自初次提交以来，我们生成了新信息，该信息表明426C核心引起抗体 在配置的N连接糖基化位点N276上旁路聚糖，这是主要障碍之一 防止种系VRC01级抗体被广泛中和。我们将测试我们的建议 通过迭代方法通过良好的实验进行策略。我们提供支持的初步数据 我们的整体方法。