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.