HIV and SIV Envelope Glycoproteins

HIV 和 SIV 包膜糖蛋白

• 批准号: 7283489
• 负责人: KENNETH H ROUX
• 金额: $ 36.15万
• 依托单位: FLORIDA STATE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2003
• 资助国家: 美国
• 起止时间: 2003-04-01 至 2012-01-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7283489
• 关键词: Acquired Immunodeficiency Syndrome; Antibodies; Antigen-Antibody Complex; Applications Grants; Area; Arts; Binding; Binding Sites; Biology; Cells; Complex; Constitution; Crystallography; Development; Diagnostic Reagent; Disease; Electrons; Epitopes; Fostering; Freezing; Glycoproteins; Goals; HIV; HIV Envelope Protein gp120; HIV-1; HIV-2; Image; Immune system; In Situ; Individual; Infection; Investigation; Knowledge; Ligands; Lipids; Location; Maps; Mediating; Membrane Glycoproteins; Membrane Proteins; Methodology; Microscopic; Modeling; Modification; Molecular; Monoclonal Antibodies; Morphology; Numbers; Pathogenesis; Peptides; Positioning Attribute; Process; Protein Binding; Proteins; Public Health; Reaction; Recombinants; Relative (related person); Resolution; SIV; Specimen; Staging; Structure; Surface; Techniques; Therapeutic Agents; Uncertainty; Vaccines; Viral; Virion; Virus; Virus-like particle; comparative; design; env Gene Products; improved; monolayer; novel strategies; particle; three-dimensional modeling; tomography; urinary gonadotropin fragment

DESCRIPTION (provided by applicant): Detailed knowledge of the structural and functional aspects of the molecules involved in the interaction, binding, and fusion of HIV-1 and the closely related SIV with their target cells is fundamental to our understanding of the disease processes in AIDS and to the rational design of diagnostic reagents, vaccines and other therapeutic agents. Two of the most important molecules in the infectious process, namely the envelope glycoproteins (Env) glycoproteins, SU (surface), and TM (transmembrane), are only partially characterized at the structural level with many of their important features still poorly defined. These areas of uncertainty include the orientation of the variable loops, some of the structural changes that occur during the binding and fusion processes, and the features which foster or inhibit Ab-mediated neutralization. Another area of uncertainty involves the distribution Env proteins on viral particles of various types and developmental stages. This proposal describes investigations aimed at applying new approaches for the determination of the 3D morphology of the HIV-1, HIV-2, and SIV envelope (Env) surface (SU, gp120) and transmembrane (TM, gp41) regions as they are expressed on the viral surface and in purified recombinant form. Our goals are to determine the numbers, locations, orientations, and structural details of Env spikes, both alone and in complex with monoclonal antibodies and ligands, on the surface of various forms of HIV and SIV viral particles. In addition we will expand upon our previous epitope and reactive-site mapping studies of individual molecules and complexes by conducting 3D structural analyses on 2D arrays of recombinant soluble trimeric Env proteins and immune complexes. The primary methodologies will be the analysis of intact virions by state-of-the-art cryo-electron microscopic (cryoEM) tomography and computationally assisted model building, including fitting of previoulsy described atomic structures into our 3D models. Relevance to Public Health: The grant proposal is designed to provide key information on the AIDS viral surface proteins that are responsible for infection. These proteins also are the targets of the immune system's antibody defenses against AIDS. The information provided could help in the design of therapeutic agents and vaccines.

描述（由申请人提供）：详细了解HIV-1相互作用，结合和融合的分子的结构和功能方面以及与其靶细胞密切相关的SIV与我们对艾滋病中疾病过程以及诊断，疫苗，疫苗和其他治疗剂的合理设计的理解至关重要。传染过程中最重要的两个分子，即包络糖蛋白（ENV）糖蛋白，SU（SUSTARE）和TM（跨膜），仅在结构水平上部分地表征其许多重要特征，其许多重要特征仍然不当定义。这些不确定性领域包括可变回路的方向，结合和融合过程中发生的一些结构变化以及促进或抑制AB介导的中和的特征。不确定性的另一个领域涉及各种类型和发育阶段的病毒颗粒上的分布ENV蛋白。该提案描述了旨在应用新方法来确定HIV-1，HIV-2和SIV INVELOPE（ENV）表面（SU，GP120）和跨膜（TM，GP41）区域的新方法，因为它们是在病毒表面上表达的，并以纯化的重组形式表达。我们的目标是在各种形式的HIV和SIV病毒颗粒的表面上，确定单独和与单克隆抗体和配体的Env Spikes的数量，位置，方向和结构细节。此外，我们将通过对重组可溶性三聚体emb蛋白和免疫复合物的2D阵列进行3D结构分析来扩展单个分子和复合物的反应点映射研究。主要的方法将是对最先进的冷冻电子显微镜（冷冻）层析成像和计算辅助模型构建的完整病毒体的分析，包括将Previoulsy描述的原子结构拟合到我们的3D模型中。与公共卫生的相关性：赠款提案旨在提供有关导致感染的艾滋病病毒表面蛋白质的关键信息。这些蛋白质也是免疫系统针对艾滋病的抗体防御措施的靶标。提供的信息可能有助于设计治疗剂和疫苗。