GENETIC VACCINES AGAINST HIV MUTANTS

描述：鉴于HIV在地球仪上的广泛序列差异， 及其在单个人体内发生变异的可怕能力，疫苗 交叉反应性免疫反应的小库将限制 效用 鉴于艾滋病毒疫苗的迫切需要， 将开发出能产生交叉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） 多突变体疫苗;和3）DNA改组疫苗。 在多基因 在这种方法中，宿主暴露于不同蛋白质的混合物， 病原体希望保守的表位将产生保护性 针对其他艾滋病毒变异体的反应。 对于多突变体方法， 来自几个病毒分离株或进化枝的一种抗原的代表是 用于疫苗产生交叉保护。 虽然多基因和 多突变体方法具有产生交叉保护的能力， 免疫反应，既没有一个积极的机制，预测 新出现的艾滋病毒变种。 为了更好地预测这些新出现的变体，我们 将使用DNA改组重组和突变目前的艾滋病毒分支， 具有扩大的产生能力的新表位群体 交叉反应。 为了实现这些目标，以下具体目标 将在HLA-A*0201转基因小鼠中进行检测：特异性目的1。 多基因 疫苗 描述细胞毒性T淋巴细胞（CTL）的多样性， HIV-1 ELI文库产生的抗体应答。 具体目标2。 多突变疫苗。 表征交叉进化枝免疫水平 由GP 160进化枝代表产生的响应。 具体目标3。 免疫 竞争与对抗。 确定可能的干扰水平 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 描述交叉进化枝免疫反应的特征 由通过DNA改组突变的gp 160进化枝代表产生。 以来 疫苗将在HLA-A*0201转基因小鼠中进行测试，这将允许 直接翻译这些项目中获得的信息， 翻译成人类。 如果这三个目标实现了， 可以将多层疫苗结合起来， 有能力交叉保护现有的艾滋病毒分支和那些将 在未来几年出现。 这些疫苗也可能具有治疗潜力， 在关闭艾滋病病毒在感染者体内的突变逃逸途径方面， 单独的.

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.