PREVENTIVE AND THERAPEUTIC PEPTIDE AIDS VACCINES

这个项目建立在一个现有的程序，已经产生了 一种基于多种肽衍生的新型疫苗的令人兴奋的结果 来自与PPD缀合的gp 120的V3结构域。最值得注意的是， 在动物中，产生高滴度的初级分离株， 抗体和HIV +疫苗中的血浆HIV水平大幅降低， 与中和抗体滴度的大幅增加相关 针对V3环表位。该系统利用了 BCG预免疫受试者和动物中的PPD。基于这些观察 似乎这种疫苗比任何一种 已报告数据的其他艾滋病毒疫苗。我们认为 尽管在产生针对env的有效抗体方面存在困难 在过去的地区，这些领域实际上是主要的中和 体内靶向。我们现在建议将这种方法扩展到1）开发 改进的V3肽和gp 41疫苗缀合物，其集中于PPD和 M.结核病，2）评估假设 PDD作为一种独特的疫苗载体， 用于改善缀合物的免疫原性。3)测试V3的实用性 环和gp 41肽鸡尾酒疫苗预防HIV感染 在动物模型中，包括转基因hu CD 4/CCR 5小鼠，SCID-hu小鼠， HIV阳性黑猩猩和HIV血清阴性和 艾滋病毒阳性志愿者。我们认为，这是一个可行的办法， 开发有效的艾滋病毒疫苗， 目的由于我们的初步疫苗已经在一个 小规模的人类临床试验，额外的实验， 现在可以接种疫苗了。此外，假设的改善， 疫苗实际上可以在短时间内被纳入疫苗中， 时间

This project builds upon an existing program that has already generated exciting results with a novel vaccine, based on multiple peptides derived from the V3 domain of gp120 conjugated to PPD. Most notably, we observed in animals the generation of high titered primary isolate neutralizing antibodies and in HIV + vaccines major reduction in plasma HIV levels that were correlated with substantial increases in titers of neutralizing against V3 loop epitopes. This system utilizes the potent adjuvanticity of PPD in BCG-preimmunized subjects and animals. Based on these observations it appears that this vaccine has demonstrated more effectiveness than any other HIV vaccine for which data have been reported. We believe that despite difficulties in generating effective antibodies against env regions in the past, these domains are in fact the major neutralizing target in vivo. We now propose to expand this approach to 1) develop improved V3 peptide and gp41 vaccine conjugates focusing on PPD and various recombinant proteins of M. tuberculosis, 2) evaluate hypothesis for the mechanisms of action of PDD as a unique vaccine carrier to allow for improvement of conjugate immunogenicity. 3) Test the utility of V3 loop and gp41 peptide cocktail vaccines in the prevention of HIV infection in animal models, including transgenic hu CD4/CCR5 mice, SCID-hu mice, HIV+ chimpanzees and in limited clinical trials in HIV seronegative and HIV + volunteers. We believe that this is a feasible approach towards the development of effective HIV vaccines for preventative and therapeutic purposes. Since our preliminary vaccine has already shown efficacy in a small scale human clinical trials, additional experiments with this vaccine can be done now. Moreover, the hypothesized improvements to the vaccine realistically can be incorporated into the vaccine within a short time.