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: 9282390
• 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/9282390
• 关键词: AIDS Vaccines; Academic Medical Centers; Amino Acid Substitution; Animals; Antigens; Autologous; Binding; Bioinformatics; Biological Assay; Cells; Cleaved cell; Clinical Trials; Collaborations; Communication; Complex; Cryoelectron Microscopy; Crystallization; Development; Epidemic; Epitopes; Evolution; Generations; Genes; Genetic; Genotype; Glycoproteins; Goals; HIV Envelope Protein gp120; HIV-1; HIV-1 vaccine; Health; Heterogeneity; Human; Hydrogen; Immune system; Immunization; Immunologics; 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; Roentgen Rays; Serologic tests; Site; Social Welfare; Structure; Testing; Vaccine Research; Vaccines; Variant; Virion; Virus; Virus Activation; Woman; Work; X ray diffraction analysis; X-Ray Crystallography; X-Ray Diffraction; base; biophysical tools; design; env Gene Products; env Genes; experience; experimental study; immunogenicity; improved; insight; medical schools; men; milligram; neutralizing antibody; programs; prophylactic; 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（由申请方提供）：项目1的目标是基于一系列HIV- 1基因设计和评价SOSIP gp 140三聚体的新版本，并纳入旨在改善其结构、抗原性和免疫原性的各种序列修饰。在项目1中设计的三聚体，以及来自项目2的基于基本结构的输入，将由核心A生产，提供给项目2进行结构研究，在项目1中评估抗原性和其他性质，并发送给多个外部研究中心。 合作者进行额外的研究，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。约翰P.摩尔博士，艾滋病防治和发展方案的主要负责人，将指导项目1，该项目将设在威尔康奈尔医学院（WCMC），纽约。摩尔博士将与罗吉尔W.桑德斯将领导阿姆斯特丹学术医学中心的一个组成部分。项目1的具体目的是：目的1：改进目前最先进的SOSIP三聚体BG 505 SOSIP.664的设计，用于结构和免疫原性研究。我们将设计新的SOSIP三聚体使用高分辨率X射线和冷冻电镜结构和动物免疫原性研究的信息。我们将创建针对bNAb的种系祖先的变体三聚体，以及基于婴儿-BG 505内的序列进化的连续三聚体。其他目标是减少三聚体异质性，从而提高结晶潜力，掩蔽可能充当免疫诱饵的非NAb表位，更好地将bNAb表位呈递给免疫系统，并驱动Ab进化为bNAb。目的2：鉴定来自不同遗传亚型的多种SOSIP三聚体，其性质与BG 505 SOSIP.664相当。我们将结合联合收割机在三聚体设计方面积累的经验、我们对基于BG 505的三聚体（A亚型）性质的了解以及生物信息学方法，以鉴定和/或设计基于其他亚型（特别是B和C亚型）的新变体。我们的目标是创建一个配方，使我们能够从许多/大多数基因型中制备高质量的SOSIP三聚体，从而扩大两个项目中基于疫苗和结构研究的三聚体范围。目的3：设计和帮助评估使用SOSIP三聚体的免疫原性研究。HIVRAD团队已经与几个团体建立了合作关系，包括但不限于CHAVI-ID和IAVI，为动物免疫研究提供基于三聚体的免疫原，作为人类临床试验途径的一部分。项目1小组将与相关合作者共同设计具体的实验，HIVRAD的内部指导委员会将参与其中，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应用的总体目标是帮助开发一种预防性HIV-1疫苗，该疫苗基于通过合理设计的、结构相关的包膜糖蛋白三聚体诱导病毒中和抗体。核心A将制作项目1和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。应用程序的目标与公共卫生和人类福利高度相关。