COMBINED VACCINE STRATEGIES FOR THE PREVENTION OF AIDS

这项计划的长期目标是开发有效的 使用新型重组病毒载体的艾滋病毒疫苗。朝向这个方向 最后，这项建议的目的是为了更好地了解 人类免疫缺陷病毒的保护性免疫反应及新型抗原的设计 构型和改进的载体以诱导这些保护性免疫 回应。这一计划的综合项目有五大具体 目标： 1.比较以下人群对艾滋病毒的免疫应答 表现出长期非进展性艾滋病毒感染 艾滋病毒感染的正常发展。 2.修改艾滋病毒和SIV基因以增强抗原提呈， 将这些改变的基因插入痘病毒载体，并评估 这些重组病毒在啮齿动物体内。这些修改的目的是 增加蛋白质处理，增强或重定向细胞内 运输，或暴露隔离表位。共刺激分子将 被纳入以增强细胞免疫反应。 3.表达编码能中和HIV的有效抗体的基因。基因 编码广谱中和抗体将被插入重组 腺相关病毒可传递高水平的中和抗体 对发行量的影响。 4.改进的活重组病毒载体的发展和更好的 艾滋病疫苗的动物模型。载体包括腺相关病毒， 非复制型痘病毒和复制痘病毒--缺乏因子的病毒 参与逃避宿主的免疫反应。一个SCID小鼠模型将是 改进以增强植入并允许诱导初级免疫 回应。 5.设计和制造用于临床的新型候选艾滋病疫苗 在人体上进行试验。将生产第二代疫苗 立即，根据目前的知识。第三代疫苗将是 在积累了相关的附加信息后设计 免疫、最佳抗原构象、与免疫调节剂的组合 分子，以及病毒载体的改进。

The long-term objective of this program is the development of effective vaccines against HIV using novel recombinant viral vectors. Toward this end, the goals of this proposal are to attain a better understanding of the protective immune responses against HIV and to design novel antigen configurations and improved vectors to elicit these protective immune responses. The combined projects of this program have five major specific aims: 1. Comparison of the immune responses against HIV in individuals that exhibit long-term non-progressive HIV infection with those that have normal progression of HIV infection. 2. Modification of HIV and SIV genes to enhance antigen presentation, insertion of these altered genes into poxvirus vectors, and assessment of these recombinant viruses in rodents. Such modifications are aimed at increasing protein processing, enhancing or redirecting intracellular transport, or exposing sequestered epitopes. Co-stimulatory molecules will be included to enhance cellular immune responses. 3. Expression of genes encoding potent antibodies to neutralize HIV. Genes encoding broadly neutralizing antibodies will be inserted into recombinant adeno-associated virus to deliver high levels of neutralizing antibodies to the circulation. 4. Development of improved live recombinant viral vectors and better animal models for AIDS vaccines. Vectors include adeno-associated virus, non-replicating pox-viruses and replication pox-viruses that lack factors involved in evading the host immune response. A scid mouse model will be improved to enhance engraftment and allow induction of primary immune responses. 5. Design and manufacture of new candidate AIDS vaccines for clinical trials in humans. Second-generation vaccines will be generated immediately, based on current knowledge. Third-generation vaccines will be designed after accumulating additional information on correlates of immunity, optimal antigen conformation, combinations with immunomodulatory molecules, and viral vector improvements.