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

项目总结/摘要 艾滋病是一种可预防的疾病，但根据世界卫生组织的统计， 联合国艾滋病规划署一种能产生抗HIV-1的广泛中和抗体（bNAb）的疫苗将是最好的方法， 虽然预防艾滋病大流行病的方法是有效的，但迄今为止还没有开发出有效的疫苗。 以前设计基于抗体的疫苗的努力一直不成功，部分原因是由于有限的 当时关于HIV-1颗粒、其感染机制和抗HIV-1抗体的可用信息 感染者的反应。该领域的最新进展为疫苗开发开辟了新的途径 设计，我们将调查的一部分，这项建议的研究。我们最近的研究表明， 使用单一包膜（Env）免疫原的疫苗接种策略不适合引发抗HIV-1 相反，新的顺序免疫策略引起了显着的中和抗体， 在具有有限抗体库的敲入小鼠模型中的效力和广度。在这份提案中，我们的目标是 设计和评估新的免疫原和序贯免疫策略，以诱导bNAb， 具有完整免疫球蛋白（IG）库的动物模型。具体而言，我们计划：1）测试新的 免疫原和序贯免疫方案以引发针对a）中Env的V3-N332表位的bNAb 野生型小鼠，B）携带人IG基因座的AlivaMA B小鼠和c）表达人末端的小鼠 脱氧核苷酸转移酶（Tdt）作为更接近类似于人IG库的模型;和 2)记录了V3-N332 bNAb早期阶段V3-N332表位上聚糖的需求 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， 序贯免疫，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， 与加州理工学院的比约克曼实验室合作。团体和机构都将提供一个优秀的 环境和所有必要的资源来进行这项建议的研究。努森茨韦格 该实验室有一个长期和巩固的轨迹研究B细胞和HIV-1。Bjorkman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， HIV-1。Bjorkman集团的工作完美地补充了Nussenzweig的专业领域 实验室，并提供了一个最佳的情况下，这项建议的研究。培训期间， K99阶段在这种极好的环境中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.