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

项目摘要/摘要 艾滋病是一种可以预防的疾病，但每年仍有数百万新感染病例发生。 联合国艾滋病规划署。产生针对HIV-1的广谱中和抗体(BNAbs)的疫苗将是最好的方法 防止艾滋病大流行的蔓延，然而，到目前为止还没有研制出有效的疫苗。 以前设计基于抗体的疫苗的努力都没有成功，部分原因是 当时有关HIV-1颗粒、其感染机制和抗HIV-1抗体的信息 在受感染的个体中引起的反应。该领域的最新进展为疫苗开辟了新的途径 我们将作为此提案研究的一部分进行调查的设计。我们最近的研究表明，常见的 基于单一包膜(Env)免疫原的疫苗接种策略不适合诱导抗HIV-1 相反，新的顺序免疫策略诱导了显著的中和抗体 具有限制性抗体库的敲入小鼠模型的效力和广度。在这项提案中，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bNAbs在 具有完整免疫球蛋白(Ig)谱的动物模型。特别是，我们计划：1)测试新的 免疫原和序贯免疫方案在a)中诱导针对env 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)表达人末端的小鼠 脱氧核苷酸转移酶(TDT)作为更接近人类免疫球蛋白谱系的模型；以及 2)记录V3-N332 bNAb早期阶段糖链对V3-N332表位的要求 发展。拟议的研究结果将为疫苗的设计提供有价值的信息。 对抗HIV-1。这项工作还将告知管理抗体成熟过程的一般规则 顺序免疫，可促进针对其他无关病原体的疫苗设计。这个 该提案的K99阶段将于#年在洛克菲勒大学的Nussenzweig实验室进行 与加州理工大学比约克曼实验室的合作。集团和机构都将提供杰出的 环境和开展这项建议研究的一切必要资源。努森茨韦格 实验室对B细胞和HIV-1的研究有一个漫长而坚实的轨迹。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 作为HIV-1。比约克曼小组的工作完美地补充了努森茨韦格的专业领域 实验室，并为这一提议的研究提供了一个最佳方案。在培训期间接受的培训 在这个可怕的环境中，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.