TARGETED MUCOSAL VACCINES AGAINST HIV 1

这个项目的主要目标是增强抗体和T细胞 对HIV-1粘膜亚单位疫苗的反应。为了实现这一目标，我们正在 利用大肠杆菌不耐热肠毒素(LT)靶向嵌合体 HIV-1蛋白进入粘膜表面。因为没有一个被接受的单一 保护性免疫的相关性，我们的研究将同时进行细胞和 以及粘膜免疫后的体液反应。要增加T 细胞反应，我们已经开发了用来取代LT片段的系统 HIV-1蛋白的表位以选择性地传递这些表位 与类相交的细胞质隔室的决定因素 I MHC抗原处理途径。这些嵌合体的能力 在这一途径中诱导和激发反应的蛋白质将被评估 在小鼠和猴子模型中，特别强调 刺激分泌β-趋化因子的T细胞的反应。此外, 我们已经开发了一种新的真核表达系统，它允许 LT-Env嵌合体的正确折叠有望引发有效 粘膜免疫后中和抗体反应。这些嵌合体 将在小鼠和猴子模型中进行评估，重点是 诱导中和HIV-1初级分离株的抗体。

The principal goal of this project is to enhance antibody and T cell responses to HIV-1 mucosal subunit vaccines. To achieve this goal, we are using the Escherichia coil heat-labile enterotoxin (LT) to target chimeric HIV-1 proteins to mucosal surfaces. Because there is no single accepted correlate of protective immunity, our studies will pursue both cellular and humoral responses that follow from mucosal immunization. To augment T cell responses, we have developed systems to replace segments of LT with epitopes of HIV-1 proteins in order to selectively deliver these determinants to the cytoplasmic compartment that intersects with the Class I MHC antigen processing pathway. The abilities of these chimeric proteins to induce and elicit responses in this pathway will be evaluated in murine and monkey models, with special emphasis being placed on responses that call up T cells that secrete beta-chemokines. In addition, we have developed a novel eukaryotic expression system that allows the proper folding of LT-Env chimeras that are expected to elicit potent neutralizing antibody responses after mucosal immunization. These chimeras will be evaluated in murine and monkey models with emphasis on the induction of antibodies that neutralize primary isolates of HIV-1.