PREVENTIVE AND THERAPEUTIC PEPTIDE AIDS VACCINES

此项目建立在已生成的现有程序的基础上 一种基于多肽的新型疫苗取得了令人兴奋的结果 从gp120的V3结构域与PPD结合。最值得注意的是，我们观察到 在动物中产生高滴度的初级中和分离物 抗体和HIV+疫苗显著降低了血浆HIV水平， 与中和滴度的大幅增加有关 与V3环表位进行比对。这个系统利用了强辅助性。 卡介苗预免疫受试者和动物的PPD。基于这些观察 这种疫苗似乎比以往任何一种疫苗都显示出更好的效果。 已报告数据的其他艾滋病毒疫苗。我们相信 尽管在产生针对环境的有效抗体方面存在困难 在过去的区域中，这些领域实际上是主要的中和 活体靶标。我们现在建议将这种方法扩展到1)开发 改进的V3多肽和gp41疫苗结合物专注于PPD和 结核分枝杆菌的各种重组蛋白，2)评价假说 对于PDD作为一种独特的疫苗载体的作用机制 用于提高结合免疫原性。3)测试V3的实用性 环状疫苗和gp41多肽鸡尾酒疫苗预防HIV感染的研究 在动物模型中，包括转基因HU CD4/CCR5小鼠，SCID-HU小鼠， HIV阳性的黑猩猩和有限的临床试验中HIV血清阴性和 HIV+志愿者。我们认为，这是一种可行的方法， 预防和治疗用有效HIV疫苗的研制 目的。由于我们的初步疫苗已经在 小规模的人体临床试验，与此相关的额外实验 现在可以接种疫苗了。此外，假想的对 疫苗实际上可以在很短的时间内被纳入疫苗 时间到了。

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.