RATIONAL PEPTIDE COMPONENT VACCINES FOR AIDS

艾滋病合理肽成分疫苗

• 批准号: 3140806
• 负责人: Kemp Bailey Cease
• 金额: $ 19.15万
• 依托单位: UNIVERSITY OF MICHIGAN AT ANN ARBOR
• 依托单位国家: 美国
• 财政年份: 1989
• 资助国家: 美国
• 起止时间: 1989-03-01 至 1994-02-28
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/3140806
• 关键词: AIDS; AIDS vaccines; B lymphocyte; CD4 molecule; HIV envelope protein gp120; HIV infections; T lymphocyte; antibody receptor; antibody specificity; antigen presentation; cellular immunity; chemical structure function; enzyme linked immunosorbent assay; genetic manipulation; human immunodeficiency virus; molecular cloning; peptides; synthetic vaccines; viral pneumonia; virus envelope; virus protein; AIDS; AIDS vaccines; B lymphocyte; CD4 molecule; HIV envelope protein gp120; HIV infections; T lymphocyte; antibody receptor; antibody specificity; antigen presentation; cellular immunity; chemical structure function; enzyme linked immunosorbent assay; genetic manipulation; human immunodeficiency virus; molecular cloning; peptides; synthetic vaccines; viral pneumonia; virus envelope; virus protein

Immunologic protection, the essence of any effective vaccine, is generally obtained by exposure to an agent that simulates disease experience immunologically. In the case of infection with the AIDS virus, it is not clear that disease experience itself results in effective immunity that could confer protection. Through one immunologic parameter of specific immunity, the presence of neutralizing antibody, may correlate with a more favorable short term clinical course in some risk groups, overall, the immunologic prerequisites for protection against AIDS remain unknown. The goal of any potential AIDs vaccine must, therefore, be to induce the strongest possible T cell and B cell immunity in an individual prior to exposure to the AIDS virus or infected cells. Experience from murine and feline retroviruses suggests that immunity to the envelope proteins may be most important for protection. However, the AIDs virus gp120 envelope protein shows substantial variability in the distinct isolates sequenced to date. Consequently a generally effective enveloped-directed vaccine will need to incorporate the important B cell and T cell epitopes from all isolates in the form of highly immunogenic proteins or peptides. This project will systematically analyze peptides representing important T cell sites in gp120 and use the insights gained, to develop highly immunogenic peptide component vaccine constructs for AIDS. The initial site to be intensively studied will be the env T1 site that my collaborators and I recently reported. Each site will be examined in four phases. In Phase 1 studies, the limits of the site will be carefully determined and the minimal peptide with full immunologic activity identified. In Phase 2 studies, the stringency of recognition of the site will be examined by systematically identifying and characterizing critical residues. Cross-recognition of the site as it exists in all sequenced isolates of the AIDs virus worldwide will be carefully characterized as will important practical substitutions that simplify handling and facilitate use as a component in a vaccine construct. In phase 3, the potentially important antibody response to these T-cell sites will be examined in detail. Finally, in Phase 4, the structure-activity insights from Phases 1-3 will be used to select peptide components to be used, along with B cell sites characterized by others, in developing peptide component vaccine constructs. Through repeated design, synthesis and testing, constructs will be engineered with the desired immunologic activity. The optimized peptide component vaccine constructs that emerge should reveal important principles for engineering synthetic or recombinant vaccines against AIDS and will themselves be candidates for continuing preclinical studies.

免疫保护是任何有效疫苗的本质，是 通常通过暴露于模拟疾病的药物来获得 在免疫学上经验。 在艾滋病感染的情况下 病毒，尚不清楚疾病经历本身会导致 有效的免疫力可以提供保护。 通过一个 特定免疫的免疫学参数，存在 中和抗体可能与更有利的短相关 总体而言，某些风险组的术语临床课程是免疫学的 保护艾滋病的先决条件仍然未知。 因此，任何潜在艾滋病疫苗的目标都必须是 在A中诱导最强的T细胞和B细胞免疫 在暴露于艾滋病病毒或感染细胞之前的个体。 鼠和猫逆转录病毒的经验表明 对信封蛋白的免疫力可能对 保护。 但是，AIDS病毒GP120包膜蛋白显示 迄今为止测序的不同分离株的实质变异性。 因此，一种通常有效的包裹导向的疫苗将 需要从 所有分离株以高度免疫原性蛋白或 肽。 该项目将系统地分析代表的肽 GP120中重要的T细胞位点，并使用所获得的见解 开发高度免疫原性的肽成分疫苗构建体 艾滋病。 最初要深入研究的站点将是Env 我和我的合作者最近报道的T1网站。 每个站点 将在四个阶段进行检查。 在第1阶段研究中，限制 将仔细确定该地点的位置，并最小 确定了完全的免疫学活动。 在第二阶段研究中， 对网站的认可的严格性将由 系统地识别和表征关键残基。 在所有测序中都存在该站点的交叉认可 全球艾滋病病毒的分离株将仔细 特征是重要的实用替代 简化处理并促进用作疫苗的组件 构造。 在第3阶段，潜在的重要抗体反应 这些T细胞网站将进行详细检查。 最后，在 第4阶段，阶段1-3的结构活动见解将为 用于选择要使用的肽成分，并与B细胞一起使用 在开发肽成分时，以他人为特征的站点 疫苗构建体。 通过重复设计，合成和 测试，结构将通过所需的免疫学设计 活动。 优化的肽成分疫苗构建体 出现应揭示工程合成的重要原则 或针对艾滋病的重组疫苗，本身将是 继续进行临床前研究的候选人。