PROJECT 1: Design of native-like SOSIP trimers

项目 1：类似天然 SOSIP 三聚体的设计

• 批准号: 10083181
• 负责人: JOHN P MOORE
• 金额: $ 104.72万
• 依托单位: WEILL MEDICAL COLL OF CORNELL UNIV
• 依托单位国家: 美国
• 财政年份: 2015
• 资助国家: 美国
• 起止时间: 2015-06-01 至 2025-05-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10083181
• 关键词: Academic Medical Centers; Animals; Antibody Response; Antigens; Award; Biological Assay; Caliber; Chemicals; Cleaved cell; Collaborations; Consult; Contracts; Cryoelectron Microscopy; Data; Development; Elements; Epitope Mapping; Epitopes; Evolution; Funding; Genes; Goals; HIV-1; Helper-Inducer T-Lymphocyte; Immune system; Immunization; Immunologics; Lead; Letters; Masks; Modification; Mutation; Netherlands; New York; Outcome; Particulate; Polysaccharides; Process; Property; Recipe; Recording of previous events; Regimen; Research; Resolution; Roentgen Rays; Serology test; Structure; Supervision; Surface Plasmon Resonance; Testing; Vaccination; Variant; Work; base; design; env Gene Products; env Genes; experience; experimental study; immunogenic; immunogenicity; improved; iron oxide nanoparticle; medical schools; nanoparticle; neoantigens; programs; response; vaccine trial

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.

项目1 摘要 项目 1 的目标是基于一系列 HIV-1 基因设计和评估新版本的 SOSIP 三聚体 通过突变来改善其结构、抗原和免疫原性特性。三聚体设计于 项目 1 具有来自项目 2 的基于结构的输入，由核心 B 生成，提供给项目 2 以进行结构 研究，由项目 1 评估抗原性，并发送给多个合作者进行进一步研究， 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。 John P. Moore 将指导纽约威尔康奈尔医学院的项目 1。罗吉尔·W·桑德斯博士 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： 目标 1：设计可诱导 bNAb 反应的 Env 三聚体。我们将设计新的和重新设计 通过使用高分辨率结构和动物免疫原性数据来识别现有的 SOSIP 三聚体。我们将创造 针对种系 bNAb 前体 (gl-bNAb) 的 SOSIP 三聚体变体。我们将进一步提高整体水平 SOSIP 三聚体“配方”可与任何给定的 Env 序列一起使用，因为来自多个进化枝的三聚体可能是 引导 NAb 反应走向广度所必需的。我们将集中对 SOSIP 三聚体上的 bNAb 表位做出反应， 通过消除聚糖屏蔽中不需要的孔并掩盖可能充当诱饵的非 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的 bNAb 和 gl-bNAb 免疫系统的表位，并驱动抗体进化向 bNAb 发展。 目标 2：通过提出 SOSIP 来增强抗体反应的效力和持久性 三聚体颗粒免疫原并掺入 T 辅助细胞表位。我们将化学耦合 SOSIP 三聚体与氧化铁纳米粒子（NP，25-50 nm）用作引发抗体的免疫原 回应。为了弥补内源性 Env 编码的 T 细胞辅助表位的众所周知的缺陷，我们 将外源 T 细胞辅助表位整合到可溶性和 NP 呈递的 SOSIP 三聚体中。整体 目标是克服 HIV-1 包膜蛋白免疫原性的总体限制。 目标 3：使用 SOSIP 三聚体设计和评估动物免疫原性研究。我们的团队 与多个团体建立了良好的合作关系，并获得其他非 NIH 的资助支持 共同使其能够开展该奖项未直接支付的动物免疫研究。项目1 将与合作者合作设计免疫原性实验并为分析和贡献做出贡献 通过进行中和、NAb 表位作图和相关血清学来解释这些研究 化验。总体目标是进一步推进 SOSIP 三聚体和基于三聚体的疫苗接种的设计 能够诱导 bNAb 的方案。