Cleaved, stabilized HIV-1 Env trimers for structural and vaccine studies

用于结构和疫苗研究的裂解、稳定的 HIV-1 包膜三聚体

• 批准号: 10336283
• 负责人: JOHN P MOORE
• 金额: $ 68.08万
• 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 2022-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10336283
• 关键词: Academic Medical Centers; Amino Acid Substitution; Animals; Antibodies; Antibody Response; Antigens; Autologous; Binding; Biophysics; Cells; Cleaved cell; Clinical Trials; Collaborations; Communication; Complex; Cryoelectron Microscopy; Data; Development; Doctor of Philosophy; Electron Microscopy; Epitopes; Foundations; Funding; Generations; Genotype; Glycoproteins; Goals; HIV Envelope Protein gp120; HIV-1; HIV-1 vaccine; Human; Hydrogen; Immune system; Infection; Letters; Macaca; Mass Spectrum Analysis; Mediating; Negative Staining; Oryctolagus cuniculus; Outcome; Principal Investigator; Procedures; Process; Production; Property; Proteins; Reagent; Recombinant Proteins; Recombinants; Regulation; Research; Research Institute; Research Project Grants; Resolution; Respiratory Syncytial Virus Vaccines; Roentgen Rays; Scientist; Shapes; Structure; Surface; Testing; Uncertainty; United States National Institutes of Health; Vaccine Research; Vaccines; Viral; Virion; Virus; Work; X-Ray Crystallography; base; biophysical analysis; biophysical techniques; design; flexibility; immunogenicity; improved; insight; iron oxide nanoparticle; medical schools; milligram; neutralizing antibody; prevent; programs; prophylactic; prototype; response; stable cell line; trimer core; vaccine development; vaccine trial; ward

Overall Abstract This HIVRAD Program Project renewal application is made in response to PAR-18-319. It contains two Research Projects, one Scientific Core and an Administrative Core, under the direction of Principal Investigator, John P. Moore, PhD (Weill Cornell Medical College; WCMC) and co-Principal Investigator, Ian A. Wilson, PhD (The Scripps Research Institute; TSRI). The goal of the project is to further develop stable, soluble, cleaved trimeric mimics of the native Env spike (SOSIP trimers) as antigens for structural studies and as immunogens for the development of vaccines aimed at inducing broadly neutralizing antibodies (bNAbs). Our central hypothesis is that a proteolytically cleaved, soluble, trimeric form of HIV-1 Env is an appropriate structural antigen for high resolution x-ray crystallography and electron microscopy studies, and a suitable immunogen for vaccine research aimed at the induction of bNAbs. Our intent is to use structure-based information to help develop an effective, prophylactic HIV-1 vaccine (or component of a more complex vaccine) that is based on the concept of inducing sufficient titers of bNAbs. We believe that one way to accomplish this goal is to make soluble recombinant protein mimics of the native, trimeric Env spike that is present on virions, that mediates virus entry into cells and that is the target for all known bNAbs. SOSIP trimers have the desired properties and can be produced efficiently, including in the amounts and qualities required for human clinical trials. This HIVRAD project team has made excellent progress during the past 4 years, and now seeks support to continue to work together. Its research plan involves the following sub-components. Project 1: John P. Moore (and Rogier W. Sanders): Design of SOSIP trimers Project 2: Ian A. Wilson (and Andrew B. Ward): Structural studies of SOSIP trimers Core B: PJ Klasse: Production of SOSIP trimers Core A: John P. Moore: Administrative support Rogier W. Sanders of the Amsterdam University Medical Centers, Amsterdam will direct a sub-component of Project 1. Andrew B. Ward of The Scripps Research Institute will be the co-leader of Project 2. As well as the integral components of the HIVRAD team, we propose to maintain and expand an extensive network of research collaborations, and we will continue to provide SOSIP trimers and related reagents to the many scientists who request our support.

总体摘要 此 HIVRAD 计划项目更新申请是根据 PAR-18-319 提出的。它包含两个研究 项目，一个科学核心和一个行政核心，在首席研究员 John P. Moore 博士（威尔康奈尔医学院；WCMC）和联合首席研究员 Ian A. Wilson 博士（The 斯克里普斯研究所； TSRI）。该项目的目标是进一步开发稳定、可溶、裂解的三聚体 天然 Env 刺突（SOSIP 三聚体）的模拟物作为结构研究的抗原和免疫原 开发旨在诱导广泛中和抗体（bNAb）的疫苗。 我们的中心假设是，HIV-1 Env 的蛋白水解裂解、可溶性三聚体形式是一种 用于高分辨率 X 射线晶体学和电子显微镜研究的适当结构抗原，以及 适用于旨在诱导 bNAb 的疫苗研究的免疫原。我们的目的是使用基于结构的 帮助开发有效的预防性 HIV-1 疫苗（或更复杂疫苗的组成部分）的信息 这是基于诱导足够滴度的 bNAb 的概念。我们相信实现这一目标的一种方法 目标是制作病毒体上存在的天然三聚体Env刺突的可溶性重组蛋白模拟物， 它介导病毒进入细胞，是所有已知 bNAb 的靶标。 SOSIP 三聚体具有所需的 特性并可以高效生产，包括人类临床所需的数量和质量 试验。 HIVRAD 项目团队在过去 4 年中取得了出色的进展，现在寻求支持 继续共同努力。其研究计划涉及以下子部分。 项目 1：John P. Moore（和 Rogier W. Sanders）：SOSIP 三聚体的设计 项目 2：Ian A. Wilson（和 Andrew B. Ward）：SOSIP 三聚体的结构研究 核心 B：PJ Klasse：SOSIP 三聚体的生产 核心 A：John P. Moore：行政支持 阿姆斯特丹大学医学中心的 Rogier W. Sanders 将指导该项目的一个子项目 项目1。 斯克里普斯研究所的安德鲁·B·沃德 (Andrew B. Ward) 将担任项目 2 的联合负责人。 除了 HIVRAD 团队的组成部分外，我们还建议维持和扩展广泛的团队 研究合作网络，我们将继续向 许多科学家请求我们的支持。