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: 8898410
• 负责人: JOHN P MOORE
• 金额: $ 310万
• 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 2020-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8898410
• 关键词: AIDS Vaccines; Academic Medical Centers; Amino Acid Substitution; Animal Structures; Animals; Antibodies; Antigens; Autologous; Binding; Bioinformatics; Biological Assay; Cells; Cleaved cell; Clinical Trials; Collaborations; Communication; Complex; Cryoelectron Microscopy; Crystallization; Crystallography; Development; Epidemic; Epitopes; Evolution; Generations; Genes; Genetic; Genotype; Glycoproteins; Goals; HIV Envelope Protein gp120; HIV-1; Head; Health; Heterogeneity; Human; Hydrogen; Immune system; Immunization; Incidence; Individual; Infant; Infection; Institution; International AIDS; Intervention; Knowledge; Lead; Letters; Link; Masks; Mass Spectrum Analysis; Mediating; Modification; National Institute of Allergy and Infectious Disease; Negative Staining; New York; Oryctolagus cuniculus; Pathway interactions; Principal Investigator; Process; Production; Property; Public Health; Recipe; Recombinant Proteins; Research; Research Contracts; Research Institute; Research Personnel; Research Project Grants; Resolution; Respiratory Syncytial Virus Vaccines; Serologic tests; Site; Social Welfare; Structure; Testing; Vaccine Research; Vaccines; Variant; Virion; Virus; Virus Activation; Woman; Work; X-Ray Crystallography; base; biophysical tools; design; env Gene Products; env Genes; experience; immunogenicity; improved; insight; medical schools; men; milligram; neutralizing antibody; programs; prophylactic; research study; stable cell line; vaccine trial; ward

 DESCRIPTION (provided by applicant): The goals of Project 1 are to design and evaluate new versions of SOSIP gp140 trimers based on a range of HIV- 1 genes and incorporating various sequence modifications intended to improve their structural, antigenicity and immunogenicity properties. The trimers designed in Project 1, with essential structure-based input from Project 2, will be produced by Core A, provided to Project 2 for structural studies, assessed for antigenicity and other properties within Project 1, and also sent to multiple external collaborators for additional research, including immunogenicity experiments in animals (which Project 1 will also be involved in analyzing). Project 1 will, therefore, be intimately involved inthe scientific program of the entire HIVRAD. Dr. John P. Moore, the PI of the HIVRAD, will direct Project 1, which will be based at the Weill Cornell Medical College (WCMC), New York. Dr. Moore will work closely with Dr. Rogier W. Sanders, who will lead a component at the Academic Medical Center, Amsterdam. The Specific Aims of Project 1 are: Aim 1: To improve the design of the currently most advanced SOSIP trimers, BG505 SOSIP.664, for structural and immunogenicity studies. We will design new SOSIP trimers using information from high-resolution x-ray and cryo-EM structures and animal immunogenicity studies. We will create variant trimers that target germline ancestors for bNAbs, and sequential trimers based on sequence evolution within infant-BG505. Other goals are to reduce trimer heterogeneity and thereby improve crystallization potential, mask non-NAb epitopes that may act as immunological decoys, better present bNAb epitopes to the immune system, and drive Ab evolution toward the development of bNAbs. Aim 2: To identify multiple SOSIP trimers from different genetic subtypes with properties comparable to BG505 SOSIP.664. We will combine our accumulated experience of trimer design, our knowledge of the properties of the BG505-based trimers (subtype A), and a bioinformatics approach, to identify and/or design new variants based on other subtypes, particularly B and C. The goals are to create a recipe that will enable us to make high quality SOSIP trimers from many/most genotypes and thereby expand the range of trimers available for vaccine- and structure-based studies in both Projects. Aim 3: To design and help evaluate immunogenicity studies using SOSIP trimers. The HIVRAD team has established collaborations with several groups, including but not limited to CHAVI-ID and IAVI, to provide trimer-based immunogens for animal immunization studies as part of the pathway towards human clinical trials. The Project 1 team will jointly design specific experiments with the relevan collaborators, with the involvement of the HIVRAD's Internal Steering Committee, and will contribute to the analysis of the studies by performing neutralization and related serology assays. RELEVANCE: The overall objective of this multi-site HIVRAD application is to help develop a preventative HIV-1 vaccine based on the induction of virus neutralizing antibodies by rationally designed, structurally relevant envelope glycoprotein trimers. Core A will make the SOSIP trimers designed in Projects 1 and 2, and provide them to both project teams and external collaborators. The goals of the application are highly relevant to public health and human welfare.

 描述（由申请人提供）：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 gp140 三聚体，并纳入旨在改善其结构、抗原性和免疫原性特性的各种序列修饰。项目 1 中设计的三聚体，以及来自项目 2 的基本结构输入，将由核心 A 生产，提供给项目 2 进行结构研究，评估项目 1 内的抗原性和其他特性，并发送到多个外部 合作者进行其他研究，包括动物免疫原性实验（项目 1 也将参与分析）。因此，项目 1 将密切参与整个 HIVRAD 的科学计划。 HIVRAD 的 PI John P. Moore 博士将指导项目 1，该项目将设在纽约威尔康奈尔医学院 (WCMC)。 Moore 博士将与 Rogier W. Sanders 博士密切合作，后者将领导阿姆斯特丹学术医学中心的一个部门。项目 1 的具体目标是： 目标 1：改进目前最先进的 SOSIP 三聚体 BG505 SOSIP.664 的设计，用于结构和免疫原性研究。我们将利用高分辨率 X 射线和冷冻电镜结构以及动物免疫原性研究的信息设计新的 SOSIP 三聚体。我们将创建针对 bNAb 种系祖先的变体三聚体，以及基于婴儿 BG505 内序列进化的序列三聚体。其他目标是减少三聚体异质性，从而提高结晶潜力，掩盖可能充当免疫诱饵的非 NAB 表位，更好地将 bNAb 表位呈现给免疫系统，并推动抗体向 bNAb 的发展发展。目标 2：鉴定来自不同遗传亚型的多个 SOSIP 三聚体，其特性与 BG505 SOSIP.664 相当。我们将结合我们积累的三聚体设计经验、我们对基于 BG505 的三聚体（A 亚型）特性的了解以及生物信息学方法，来识别和/或设计基于其他亚型（特别是 B 和 C）的新变体。我们的目标是创建一种配方，使我们能够从许多/大多数基因型中生产高质量的 SOSIP 三聚体，从而扩大可用于疫苗和疫苗的三聚体的范围。 这两个项目中都进行了基于结构的研究。目标 3：设计并帮助评估使用 SOSIP 三聚体的免疫原性研究。 HIVRAD 团队已与多个团体（包括但不限于 CHAVI-ID 和 IAVI）建立合作，为动物免疫研究提供基于三聚体的免疫原，作为人体临床试验途径的一部分。项目 1 团队将在 HIVRAD 内部指导委员会的参与下，与相关合作者共同设计具体实验，并将通过进行中和和相关血清学测定来促进研究分析。 相关性：这种多位点 HIVRAD 应用的总体目标是通过合理设计、结构相关的包膜糖蛋白三聚体诱导病毒中和抗体，帮助开发预防性 HIV-1 疫苗。核心 A 将制造项目 1 和项目 2 中设计的 SOSIP 三聚体，并将其提供给项目团队和外部合作者。该应用程序的目标与公共健康和人类福祉高度相关。