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: 10427132
• 负责人: JOHN P MOORE
• 金额: $ 133.25万
• 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/10427132
• 关键词: Academic Medical Centers; Animals; Antibody Response; Antigens; Award; Biological Assay; Caliber; Chemicals; 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的目标是根据HIV-1基因设计和评估SOSIP三聚体的新版本 具有改善其结构，抗原和免疫原性的突变。设计的三聚机 项目1，由项目2的基于结构的输入，由Core B生产，为结构2项目2提供 研究，根据项目1评估抗原性，并发送给多个合作者进行其他研究， 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（John P.罗吉尔·W·桑德斯博士 将在阿姆斯特丹阿姆斯特丹大学医学中心领导组成部分。具体目的是： 目标1：设计可以诱导BNAB响应的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，现有的SOSIP三聚体。我们将创建 SOSIP触发变体靶向种系BNAB前体（GL-BNAB）。我们将进一步改善整体 SOSIP三聚机“食谱”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 将NAB的反应转向广度所必需的。我们将重点响应sosip三聚体的BNAB表位， 通过消除在聚糖盾牌中的不必要孔以及掩盖可能充当诱饵的非NAB表位， 在触发器基座上包括新观点。总体目标是更好地呈现成熟的BNAB和GL-BNAB 向免疫系统表达，并将AB进化推向BNAB开发。 目标2：通过呈现SOSIP来提高抗体反应的效力和耐用性 修剪特定的免疫原子并掺入T馆表位置。我们将化学夫妇 SOSIP三聚体至氧化铁纳米颗粒（NP，25-50 nm），用作免疫原作为启动抗体 回答。为了弥补内源性环境编码的T细胞辅助辅助表中众所周知的缺陷，我们 将在固体和NP呈现的SOSIP三聚体中掺入外源T细胞辅助辅助表位。总体 目标是克服对HIV-1 Env蛋白免疫原性的局限性。 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 与几个小组进行了完善的合作，并获得了其他非NIH资金支持 共同使其能够进行该奖项直接支付的动物免疫抑制研究。项目1 将与合作者合作设计免疫原性实验，并有助于分析和 通过进行神经化，NAB-典当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三聚机和基于三聚体的真空的设计 能够诱导的BNAB的方案。