Design of vaccination strategies to elicit broadly neutralizing antibodies against HIV-1

项目概要/摘要 艾滋病是一种可以预防的疾病，但据统计，每年都会出现数百万新感染者 联合国艾滋病规划署。一种能够引发针对 HIV-1 的广泛中和抗体 (bNAb) 的疫苗将是消除 HIV-1 的最佳方法。 预防艾滋病的蔓延，但迄今为止尚未研制出有效的疫苗。 之前设计基于抗体的疫苗的努力并未成功，部分原因是有限的 当时有关 HIV-1 颗粒、其感染机制和抗 HIV-1 抗体的信息 受感染个体引起的反应。该领域的最新进展为疫苗开辟了新途径 我们将作为该提案研究的一部分进行调查的设计。我们最近的工作表明，常见的 使用基于单一包膜 (Env) 的免疫原的疫苗接种策略不适合引发抗 HIV-1 bNAb；相反，新颖的序贯免疫策略引发了显着的中和抗体 具有受限抗体库的敲入小鼠模型的效力和广度。在本提案中，我们的目标是 设计和评估新的免疫原和序贯免疫策略，以在体内诱导 bNAb 具有完整免疫球蛋白 (Ig) 库的动物模型。我们特别计划：1）测试新的 a) 中的免疫原和序贯免疫方案，以引发针对 Env 的 V3-N332 表位的 bNAb 野生型小鼠，b) 携带人 Ig 基因座的 AlivaMAb 小鼠和 c) 表达人终端的小鼠 脱氧核苷酸转移酶 (Tdt) 作为更接近人类 Ig 库的模型；和 2) 记录 V3-N332 bNAb 早期阶段对 V3-N332 表位的聚糖需求 发展。拟议研究的结果将为疫苗的设计提供有价值的信息 对抗 HIV-1。这项工作还将告知有关抗体成熟过程的一般规则 顺序免疫可以促进针对其他不相关病原体的疫苗设计。的 该提案的 K99 阶段将在洛克菲勒大学的 Nussenzweig 实验室进行 与加州理工学院比约克曼实验室合作。团体和机构都将提供出色的 开展本提案研究的环境和所有必要的资源。努森茨威格号 实验室在 B 细胞和 HIV-1 方面有着长期而巩固的研究轨迹。比约克曼实验室 专门研究结构生物学，对病毒病原体的免疫识别特别感兴趣，例如 如 HIV-1。 Bjorkman 团队的工作完美补充了 Nussenzweig 的专业领域 实验室，并为该提案的研究提供了最佳场景。期间接受的培训 在这个绝佳的环境中的K99阶段无疑将推动和促进我向独立的过渡。

PROJECT SUMMARY/ ABSTRACT AIDS is a preventable disease, nevertheless millions of new infections occur every year according to UNAIDS. A vaccine that elicits broadly neutralizing antibodies (bNAbs) against HIV-1 would be the best way to prevent the spreading of the AIDS pandemic, however, no efficacious vaccine has been developed to date. Previous efforts to design an antibody-based vaccine have been unsuccessful, in part due to the limited information available at the time on the HIV-1 particle, its mechanism of infection and the anti HIV-1 antibody responses elicited in infected individuals. Recent advances in the field have opened new avenues for vaccine design that we will investigate as part of the research of this proposal. Our work recently showed that common vaccination strategies using singular Envelope (Env)-based immunogens were not suitable to elicit anti HIV-1 bNAbs; instead, novel sequential immunization strategies elicited neutralizing antibodies of remarkable potency and breadth in knock-in mouse models with a restricted antibody repertoire. In this proposal, we aim to design and evaluate new immunogens and sequential immunization strategies to elicit bNAbs in animal models that have a complete immunoglobulin (Ig) repertoire. In particular we plan to: 1) test new immunogens and sequential immunization regimens to elicit bNAbs against the V3-N332 epitope of Env in a) wild type mice, b) AlivaMAb mice carrying human Ig loci and c) mice expressing the human terminal deoxynucleotidyl transferase (Tdt) enzyme as models that more closely resemble the human Ig repertoire; and 2) document the requirement of glycans on the V3-N332 epitope at the early stages of V3-N332 bNAb development. The results of the proposed research will provide valuable information for the design of a vaccine against HIV-1. This work will also inform about general rules governing the antibody maturation process upon sequential immunization that could facilitate the design of vaccines against other unrelated pathogens. The K99 phase of this proposal will take place in the Nussenzweig laboratory at The Rockefeller University in collaboration with the Bjorkman laboratory in Caltech. Both groups and institutions will offer an outstanding environment and all necessary resources to carry out the research of this proposal. The Nussenzweig laboratory has a long and consolidated trajectory studying B cells and HIV-1. The Bjorkman laboratory specializes in structural biology and is particularly interested in the immune recognition of viral pathogens such as HIV-1. The work of the Bjorkman group perfectly complements the areas of expertise of the Nussenzweig laboratory and provides an optimal scenario for the research of this proposal. The training received during the K99 phase in this terrific environment will undoubtedly propel and facilitate my transition to independence.