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

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，任何有效疫苗的本质都是 通常通过接触一种模拟疾病的试剂而获得 免疫学上的经验。在感染艾滋病的情况下 病毒，目前还不清楚疾病经历本身会导致 可以提供保护的有效豁免权。通过一次 特异性免疫的免疫学参数 中和抗体，可能与更有利的空头相关 一些风险组的长期临床病程，总体上，免疫学 预防艾滋病的先决条件尚不清楚。 因此，任何可能的艾滋病疫苗的目标都必须是 诱导最强的T细胞和B细胞免疫 个人在接触艾滋病病毒或受感染细胞之前。 来自老鼠和猫的逆转录病毒的经验表明 对包膜蛋白的免疫力可能是最重要的 保护。然而，艾滋病病毒gp120包膜蛋白显示 迄今为止测序的不同分离株具有很大的变异性。 因此，通常有效的包膜导向疫苗将 需要整合重要的B细胞和T细胞表位 所有以高免疫原性蛋白或 多肽。 这个项目将系统地分析代表 Gp120中重要的T细胞位置，并使用所获得的见解，以 开发高免疫原性多肽成分疫苗构建物 艾滋病。最初要深入研究的地点将是环境 我和我的合作者最近报告的T1站点。每个站点 将分四个阶段进行审查。在第一阶段研究中，限制 的位置将被仔细确定和最小的多肽 完全具有免疫学活性。在第二阶段研究中， 网站认可的严格程度将由以下机构审查 系统地识别和表征关键残留物。 交叉识别的网站，因为它存在于所有排序 世界各地的艾滋病病毒分离株将小心 其特点是将会有重要的实际替代 简化处理并便于作为疫苗的一个组成部分使用 建造。在第三阶段，潜在的重要抗体反应 将对这些T细胞部位进行详细检查。最后，在 阶段4，来自阶段1-3的结构-活动洞察力将是 与B细胞一起用于选择要使用的多肽成分 在开发多肽成分时，具有他人特征的位点 疫苗构建。通过反复的设计、合成和 测试，构建物将被设计成所需的免疫学 活动。优化后的多肽成分疫苗构建为 Emerge应该揭示工程合成的重要原理 或针对艾滋病的重组疫苗，它们本身将是 继续进行临床前研究的候选人。