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， 通常通过暴露于模拟疾病的试剂而获得 免疫学经验 如果感染了艾滋病 病毒，目前尚不清楚疾病的经验本身的结果， 有效的免疫力可以提供保护。 通过一个 特异性免疫的免疫学参数， 中和抗体，可能与更有利的短 总体而言，某些风险组的长期临床病程，免疫学 预防艾滋病的先决条件仍然不明。 因此，任何潜在的艾滋病疫苗的目标必须是 诱导最强的T细胞和B细胞免疫力， 在接触艾滋病病毒或受感染细胞之前， 鼠和猫逆转录病毒的经验表明， 对包膜蛋白的免疫可能是最重要的， 保护 然而，艾滋病病毒gp 120包膜蛋白显示， 迄今为止测序的不同分离株中存在大量变异。 因此，一种普遍有效的靶向疫苗将 需要将重要的B细胞和T细胞表位从 以高免疫原性蛋白形式存在的所有分离株，或 缩氨酸 该项目将系统地分析代表 gp 120中重要的T细胞位点，并利用所获得的见解， 开发高免疫原性肽组分疫苗构建体， 艾滋病 第一个要深入研究的地点将是env 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1期研究中， 将仔细确定该位点的最小肽 具有完全免疫活性。 在2期研究中， 认可该地点的严格性将由 系统地识别和表征关键残留物。 交叉识别的网站，因为它存在于所有测序 世界范围内的艾滋病病毒分离株将被小心地 其特征在于将重要的实际替代品， 简化了处理并便于用作疫苗中组分 构建体 在第3阶段，潜在的重要抗体反应 将详细检查这些T细胞位点。 最后在 第4阶段，第1-3阶段的结构-活性见解将是 用于选择待使用的肽组分，沿着B细胞 在开发肽组分中，由其他人表征的位点 疫苗构建体。 通过反复设计、合成和 测试，构建体将被工程化，具有所需的免疫学特性。 活动 优化的肽组分疫苗构建体 涌现应该揭示工程合成的重要原则 或重组疫苗， 继续临床前研究的候选人。