SALMONELLA HIV VACCINES WITH DIRECTED CELLULAR TROPISM

描述(改编自申请人的摘要)：减毒菌株 沙门氏菌已被用作人类和人类异种抗原的载体 动物疫苗接种。在小鼠中，鼠伤寒沙门氏菌被认为会感染 肠道Peyer‘s区的巨噬细胞和肝脏的细胞 还有脾。调查人员将检查对引发的 小鼠口服接种HIV p24后的免疫应答 不同工程鼠伤寒沙门氏菌的背景：(1)沙门氏菌 专门针对小鼠树突状细胞(DC)的基因工程菌株， 以及(2)一种沙门氏菌菌株，它会将抗原直接转移到 抗原提呈细胞(APC)的细胞质隔间。在第一个 在这种情况下，沙门氏菌菌株将在其表面呈现单链 针对已知的小鼠DC标志物CD11c的抗体。增强 沙门氏菌和DC的联合将导致更高效的处理 并由这些专门的APC进行演示，从而产生更好的I类 对沙门氏菌抗原和携带抗原的反应。在 第二例，沙门氏菌株将表达融合到 III型分泌蛋白，SIPC，已知可直接转位 进入宿主细胞的细胞质。这种方法将允许更有效地 P24表位的I类呈现，否则将被稀释 当p24作为可溶性细胞内递送时的沙门氏菌抗原 抗原。最后，研究人员将使用沙门氏菌疫苗株 结合了这两种新的方法来评估CTL诱导 表达人类白细胞抗原A2.1和人CD8的双转基因小鼠品系的检测 这些疫苗诱导适当免疫的潜在效力 人类的反应。这些研究的结果可能会直接 应用于生产有效的疫苗，这些疫苗可以特别 调节免疫系统以形成对艾滋病毒的保护性反应。

DESCRIPTION (Adapted from applicant's abstract): Attenuated strains of Salmonella have been used as carriers of heterologous antigens for human and animal vaccination. In mice, S. typhimurium is thought to infect macrophages in the Peyer's patches of the gut and also cells of the liver and the spleen. The investigators will examine the effect on elicited immune responses of mice orally inoculated with HIV p24 expressed in two differently engineered S. typhimurium strain backgrounds: (1) A Salmonella strain engineered to specifically target dendritic cells (DC) of the mouse, and (2) a Salmonella strain that will translocate antigen directly to the cytoplasmic compartment of an antigen-presenting cell (APC). In the first case, the Salmonella strain will present on its surface a single-chain antibody specific for the known murine DC marker, CD11c. Enhancing the association of Salmonella and DC will result in more efficient processing and presentation by these specialized APCs, thus resulting in better class I responses toward Salmonella antigens as well as carried antigens. In the second case, the Salmonella strain will express the p24 antigen fused to a type III secreted protein, SipC, which is known to be translocated directly to the cytoplasm of the host cell. This approach will permit more efficient class I presentation of p24 epitopes that otherwise would be diluted out by Salmonella antigens when p24 is delivered as a soluble intracellular antigen. Finally, the investigators will use a Salmonella vaccine strain that combines these two new approaches to evaluate CTL induction in a double-transgenic mouse line that expresses HLA-A2.1 and human CD8, to test the potential efficacy of these vaccines to elicit appropriate immune responses in humans. The results from these studies may have direct application to the production of effective vaccines that could specifically modulate the immune system to develop a protective response against HIV.