COMBINED VACCINE STRATEGIES FOR THE PREVENTION OF AIDS

该计划的长期目标是发展有效的 使用新型重组病毒载体的抗HIV疫苗。朝着这个 最后，本建议的目标是更好地了解 抗HIV保护性免疫反应和设计新的抗原 配置和改进的载体，以引发这些保护性免疫 应答该计划的组合项目有五个主要具体 目的： 1.比较个体对艾滋病毒的免疫反应， 显示长期非进行性艾滋病毒感染与那些有 HIV感染的正常进展。 2.修饰HIV和SIV基因以增强抗原呈递， 将这些改变的基因插入痘病毒载体，并评估 这些重组病毒。这些修改旨在 增加蛋白质加工，增强或重定向细胞内 运输或暴露隔离的表位。共刺激分子将 以增强细胞免疫反应。 3.表达编码有效抗体以中和HIV的基因。基因 编码广泛中和抗体的基因将被插入重组质粒中， 腺相关病毒，以提供高水平的中和抗体 到流通。 4.开发改进的活重组病毒载体和更好的 艾滋病疫苗的动物模型。载体包括腺相关病毒， 非复制型痘病毒和缺乏因子的复制型痘病毒 参与逃避宿主的免疫反应scid小鼠模型将 改进以增强植入并允许诱导初次免疫 应答 5.艾滋病临床新候选疫苗的设计和生产 人体试验第二代疫苗将产生 根据目前的知识。第三代疫苗将 在积累了关于 免疫，最佳抗原构象，与免疫调节剂的组合 分子和病毒载体的改进。

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.