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

基本信息

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
项目类别：
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

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

展开

项目摘要

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.

总体抽象此Hivrad计划项目续订应用程序是根据Par-18-319进行的。它包含两项研究在首席研究员约翰·P·约翰·P（John P.）的指导下，项目，一个科学核心和行政核心摩尔博士（Weill Cornell医学院； WCMC）和联合主管调查员，Ian A. Wilson博士（The Scripps研究所； TSRI）。该项目的目的是进一步发展稳定，可溶，切割的三聚体模仿天然Env Spike（SOSIP三聚体）作为结构研究的抗原，并作为免疫原子旨在诱导广泛中和抗体（BNAB）的疫苗的开发。我们的中心假设是一种蛋白水解的，可溶性的，三聚体的HIV-1 env是一种适当的结构抗原，用于高分辨率X射线晶体学和电子显微镜研究，A 用于诱导BNAB的疫苗研究的合适免疫原。我们的目的是使用基于结构的信息以帮助开发有效的预防性HIV-1疫苗（或更复杂的疫苗的成分）这是基于诱导足够的BNAB滴度的概念。我们相信这是实现这一目标的一种方法目的是使天然的三聚体[病毒体中存在于病毒体上的天然三聚体峰的模仿，这介导病毒进入细胞，这是所有已知BNAB的靶标。 SOSIP三聚体有所需的特性可以有效生产，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步，现在寻求支持继续一起工作。它的研究计划涉及以下子组件。项目1：John P. Moore（和Rogier W. Sanders）：Sosip Trimers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：生产SOSIP三聚机核心A：John P. Moore：行政支持阿姆斯特丹阿姆斯特丹大学医学中心的罗吉尔·W·桑德斯（Rogier W. Sanders）将指导项目1。斯克里普斯研究所的安德鲁·沃德（Andrew B. Ward）将成为项目2的共同领导者。除了Hivrad团队的组成部分，我们还建议维护和扩展广泛研究合作网络，我们将继续向SOSIP三聚体和相关试剂提供许多要求我们支持的科学家。