GENETIC VACCINES AGAINST HIV MUTANTS

针对艾滋病毒突变体的基因疫苗

• 批准号: 6163939
• 负责人: MICHAEL A BARRY
• 金额: $ 23.95万
• 依托单位: BAYLOR COLLEGE OF MEDICINE
• 依托单位国家: 美国
• 财政年份: 1998
• 资助国家: 美国
• 起止时间: 1998-03-01 至 2002-02-28
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6163939
• 关键词: AIDS vaccines; HIV envelope protein gp160; active immunization; antiviral antibody; cytotoxic T lymphocyte; genetically modified animals; human immunodeficiency virus 1; laboratory mouse; leukocyte activation /transformation; mutant; vaccine development; vector vaccine

DESCRIPTION: Given the wide sequence divergence of HIV across the globe, and its frightening ability to mutate within a single human being, a vaccine with a small repertoire of cross-reactive immune responses will have limited utility. Given the critical necessity for an HIV vaccine, this application will develop genetic vaccines that generate cross-reacting immune response by several mechanisms. We will test 1) a multi-gene vaccine; 2) multi-mutant vaccines; and 3) DNA shuffled vaccines. In the multi-gene approach, the host is exposed to a cocktail of the different protein from the pathogen in the hope that conserved epitope(s) will generate protective responses against other HIV variants. For the multi-mutant approach, representatives of one antigen from several viral isolates or clades are used in the vaccine to produce cross-protection. While both multi-gene and multi-mutant approaches have some capacity to generate cross-protective immune responses, neither has a proactive mechanism for anticipating emerging HIV variants. To anticipate these emerging variants better, we will use DNA shuffling to recombine and mutate current HIV clades into a population of novel epitopes with an expanded ability to produce cross-reactive responses. Towards these goals, the following Specific Aims will be tested in HLA-A*0201 transgenic mice: Specific Aim 1. Multi-gene vaccine. Characterize the diversity of cytotoxic T lymphocyte (CTL) and antibody responses generated by the HIV-1 ELI library. Specific Aim 2. Multi-mutant vaccines. Characterize the level of cross-clade immune responses generated by gp160 clade representatives. Specific Aim 3. Immune Competition and Antagonism. Determine the level of possible interference produced by problematic epitopes in these complex vaccines. Specific Aim 4. DNA-shuffled vaccines. Characterize the cross-clade immune responses generated by gp160 clade representatives mutated by DNA shuffling. Since the vaccines will be tested in HLA-A*0201 transgenic mice, this should allow direct translation of the information acquired in these project to be translated into humans. If these Aims are successful, then these three layers of vaccines can be combined to create a vaccine with an exceptional capacity to cross protect against existing HIV clades and those that will emerge in future years. The vaccines may also have therapeutic potential, in shutting down the avenues of mutational escape for HIV in an infected individual.

描述：鉴于艾滋病毒在全球范围内的广泛序列差异， 它在一个人体内变异的可怕能力，一种疫苗 由于有少量的交叉反应，免疫反应将是有限的 实用程序。考虑到艾滋病毒疫苗的关键必要性，这项申请 将开发产生交叉反应免疫反应的基因疫苗 通过几种机制。我们将测试1)多基因疫苗；2) 多突变疫苗；以及3)DNA改组疫苗。在多基因中 方法，宿主被暴露在不同蛋白质的鸡尾酒中 病原菌希望保守表位(S)能产生保护性 对其他艾滋病毒变种的反应。对于多突变体方法， 来自几个病毒分离株或分支的一个抗原的代表是 用在疫苗中以产生交叉保护。而多基因和 多突变体方法有一定的能力产生交叉保护 免疫反应，两者都没有主动的机制来预测 新出现的艾滋病毒变种。为了更好地预测这些新兴的变种，我们 将使用DNA改组将当前的HIV分支重组并突变为 具有扩展的生产能力的新表位的种群 交叉反应。为了实现这些目标，有以下具体目标 将在HLA-A*0201转基因小鼠中进行测试：特定目的1.多基因 疫苗。细胞毒性T淋巴细胞(CTL)和T细胞的多样性 HIV-1 ELI文库产生的抗体反应。具体目标2. 多变异疫苗。表征跨分支免疫的水平 由gp160分支代表产生的答复。特定目标3.免疫 竞争和对抗。确定可能的干扰级别 由这些复杂疫苗中有问题的表位产生。具体目标4. DNA重组疫苗。描述跨分支免疫反应的特征 由gp160产生的分支代表通过DNA改组突变。自.以来 这些疫苗将在HLA-A*0201转基因小鼠身上进行测试，这应该会允许 在这些项目中获得的信息的直接翻译 转化成人类。如果这些目标成功了，那么这三个 多层疫苗可以组合在一起，创造出一种具有特殊性能的疫苗 能够交叉保护现有的艾滋病毒分支和将 在未来的几年里出现。这些疫苗还可能具有治疗潜力， 在关闭感染艾滋病毒变异逃逸途径的过程中 个人的。