HIV neutralization and mechanisms of cellular entry

HIV 中和和细胞进入机制

• 批准号: 8552847
• 负责人: Sriram Subramaniam
• 金额: $ 90.51万
• 依托单位: DIVISION OF BASIC SCIENCES - NCI
• 依托单位国家: 美国
• 资助国家: 美国
• 起止时间: 至
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/8552847
• 关键词: AIDS/HIV problem; Acquired Immunodeficiency Syndrome; Affect; Antibodies; Antigens; Architecture; Binding; Binding Sites; Cell membrane; Cell surface; Cells; Complex; Dendritic Cells; Electrons; Epidemic; Event; Glycoproteins; Goals; HIV; HIV Envelope Protein gp120; HIV-1; Knowledge; Ligands; Maps; Mediating; Methods; Microscopic; Molecular Conformation; Molecular Structure; Relative (related person); Resolution; SIV; Spatial Distribution; Staging; Structure; Surface; Synapses; T-Lymphocyte; Therapeutic Agents; Vaccine Design; Variant; Viral; Virus; X-Ray Crystallography; cell type; combat; design; electron tomography; interest; monomer; nanometer; novel; polypeptide; receptor; stoichiometry; tool; transmission process; virological synapse

Knowledge of the molecular structure of trimeric Env on intact viruses and delineating the mechanisms of cell-cell transmission are central to the design of effective immunogens and therapeutic agents to combat HIV/AIDS. We have continued to make significant progress towards these goals over the last year. Major advances we have made over the last year include: (i) discovery of variations in the type of virological synapses involved in mediating HIV transmission between different types of cell-cell contacts including T-cell-T-cell and T-cell-dendritic cell synapses; (ii) molecular structures of trimeric HIV-1 and SIV envelope glycoproteins from a large number of viral strains and from soluble immunogens; (iii) demonstration that soluble gp140 immunogens can display the same ligand-induced changes in conformation that are seen with native envelope glycoproteins; (iv) the unexpected finding that binding of trimeric envelope glycoproteins to a co-receptor mimic alone induces the same conformational changes as binding to CD4 and (v) structural evidence, at sub-nanometer resolution, of a novel, activated intermediate state of HIV where highly conserved, interior components of the viral spike are exposed, providing a template for the design of immunogens aimed at eliciting antibodies that could block HIV entry.

了解完整病毒上三聚体Env的分子结构和描述细胞-细胞传播的机制对于设计有效的免疫原和治疗剂以对抗HIV/AIDS至关重要。 去年，我们继续在实现这些目标方面取得重大进展。我们在过去一年中取得的主要进展包括：（i）发现了参与介导HIV在不同类型的细胞-细胞接触之间传播的病毒学突触类型的变化，包括T细胞-T细胞和T细胞-树突细胞突触;（ii）从大量病毒株和可溶性免疫原中发现了HIV-1和SIV三聚体包膜糖蛋白的分子结构;（iii）证明可溶性gp 140免疫原可以显示与天然包膜糖蛋白相同的配体诱导的构象变化;（iv）三聚体包膜糖蛋白单独与共受体模拟物结合诱导与结合CD 4相同的构象变化的意外发现，和（v）结构证据，在亚纳米分辨率，一个新的，激活的中间状态的艾滋病毒，其中高度保守的，内部组件的病毒刺突暴露，提供了一个模板，旨在引发抗体，可以阻止艾滋病毒进入免疫原的设计。