PROJECT 1: Design of native-like SOSIP trimers

项目1 项目1的目标是设计和评估基于一系列HIV-1基因的SOSIP三聚体的新版本 用突变来改善它们的结构、抗原性和免疫原性。设计的三聚体 具有来自项目2的基于结构的输入的项目1由核心B产生，提供给项目2以进行结构分析。 研究，由项目1评估抗原性，并发送给多个合作者进行额外研究， 包括动物免疫原性研究。项目1将密切参与整个科学计划。博士 约翰·P·摩尔将在纽约威尔康奈尔医学院指导项目1。Rogier W.博士桑德斯 将领导阿姆斯特丹大学医学中心的一个组成部分。具体目标是： 目的1：设计可诱导bNAb应答的Env三聚体。我们将设计新的和重新设计 现有的SOSIP三聚体通过使用高分辨率结构和动物免疫原性数据。我们将创建 靶向种系bNAb前体的SOSIP三聚体变体（gl-bNAbs）。我们将进一步提高整体 用于任何给定Env序列的SOSIP三聚体“配方”，因为来自多个进化枝的三聚体可能是 需要引导NAB的反应走向广度。我们将关注对SOSIP三聚体上的bNAb表位的应答， 通过消除聚糖屏蔽物中不需要的空穴和通过掩蔽可能充当诱饵的非NAb表位， 包括三聚体碱基上的新表位。总体目标是更好地呈现成熟bNAb和gl-bNAb 表位的免疫系统，并驱动抗体进化bNAb的发展。 目的2：通过呈递SOSIP增强抗体应答的效力和持久性 三聚体颗粒免疫原和掺入辅助性T细胞表位。我们会用化学方法 将SOSIP三聚体与氧化铁纳米颗粒（NP，25-50 nm）结合，用作引发抗体的免疫原 应答为了弥补众所周知的内源性Env编码的T细胞辅助表位的缺陷，我们 将外源性T细胞辅助表位掺入可溶性和NP呈递的SOSIP三聚体中。整体 目的是克服HIV-1 Env蛋白免疫原性的一般局限性。 目的3：设计和评价使用SOSIP三聚体的动物免疫原性研究。我们的团队 与几个团体建立了良好的合作关系，并获得了其他非NIH的资金支持， 共同使其能够进行动物免疫研究，而这些研究不是由该奖项直接支付的。项目1 将与合作者一起设计免疫原性实验，并为分析做出贡献， 通过进行中和、NAb-表位作图和相关血清学来解释这些研究 测定。总体目标是进一步推进SOSIP三聚体的设计和基于三聚体的疫苗接种 能够诱导bNAb的方案。

Project 1 Abstract The goals of Project 1 are to design and evaluate new versions of SOSIP trimers based on a range of HIV-1 genes with mutations to improve their structural, antigenic and immunogenic properties. The trimers designed in Project 1, with structure-based input from Project 2, are produced by Core B, provided to Project 2 for structural studies, assessed for antigenicity by Project 1, and sent to multiple collaborators for additional research, including animal immunogenicity studies. Project 1 will be closely involved in the overall scientific program. Dr. John P. Moore, will direct Project 1, at the Weill Cornell Medical College, New York. Dr. Rogier W. Sanders will lead a component at the Amsterdam University Medical Centers, Amsterdam. The Specific Aims are: Aim 1: To design Env trimers that can induce bNAb responses. We will design new and redesign existing SOSIP trimers by using high-resolution structures and animal immunogenicity data. We will create SOSIP trimer variants that target germline bNAb precursors (gl-bNAbs). We will further improve the overall SOSIP trimer “recipe” for use with any given Env sequence, as trimers from multiple clades are likely to be necessary to steer NAb responses towards breadth. We will focus responses to bNAb epitopes on SOSIP trimers, by eliminating unwanted holes in glycan shields and by masking non-NAb epitopes that may act as decoys, including neo-epitopes on the trimer base. The overall goals are to better present mature-bNAb and gl-bNAb epitopes to the immune system, and drive Ab evolution toward bNAb development. Aim 2: To enhance the potency and durability of antibody responses by presenting SOSIP trimers particulate immunogens and incorporating T-helper epitopes. We will chemically couple SOSIP trimers to Iron Oxide nanoparticles (NP, 25-50 nm) to use as immunogens for priming antibody responses. To compensate for well-known deficiencies in endogenous Env-encoded T-cell helper epitopes, we will incorporate exogenous T-cell helper epitopes into the soluble and NP-presented SOSIP trimers. The overall goals are to overcome limitations to the immunogenicity of HIV-1 Env proteins in general. Aim 3: To design and evaluate animal immunogenicity studies using SOSIP trimers. Our team has well-established collaborations with several groups as well as access to other non-NIH funding support that together enable it to conduct animal immunization studies that are not directly paid for by this award. Project 1 will work with collaborators to design immunogenicity experiments and contribute to the analysis and interpretation of these studies by performing neutralization, NAb-epitope mapping and related serology assays. The overall goals are to further advance the design of SOSIP trimers and trimer-based vaccination regimens that are capable of inducing bNAbs.