SALMONELLA HIV VACCINES WITH DIRECTED CELLULAR TROPISM

具有定向细胞趋向性的沙门氏菌 HIV 疫苗

• 批准号: 2752140
• 负责人: FRED L HEFFRON
• 金额: $ 21.74万
• 依托单位: OREGON HEALTH & SCIENCE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 1998
• 资助国家: 美国
• 起止时间: 1998-09-30 至 2000-09-29
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/2752140
• 关键词: AIDS vaccines; CD antigens; Salmonella; attenuated microorganism; cell cell interaction; cellular immunity; chimeric proteins; dendritic cells; genetic promoter element; genetically modified animals; laboratory mouse; live vaccine; microorganism culture; microorganism immunology; molecular cloning; nonhuman therapy evaluation; vector vaccine

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.

描述（改编自申请人摘要）： 沙门氏菌已被用作人类和哺乳动物的异源抗原的载体。 动物疫苗 在小鼠中，S.鼠伤寒被认为是感染 巨噬细胞在肠道的派伊尔集合淋巴结和肝细胞 和脾脏。 研究人员将检查对诱发的 经口接种两种表达的HIV p24的小鼠的免疫应答 不同的S。鼠伤寒菌株背景：（1）沙门氏菌 经工程改造以特异性靶向小鼠树突状细胞（DC）的菌株， 和（2）沙门氏菌菌株，其将抗原直接易位至 抗原呈递细胞（APC）的细胞质区室。 上 在这种情况下，沙门氏菌菌株将在其表面呈现单链 特异于已知鼠DC标志物CD11c的抗体。 增强 沙门氏菌和DC的结合将导致更有效的处理 和介绍这些专门的APC，从而导致更好的I类 对沙门氏菌抗原以及携带的抗原的反应。 在 在第二种情况下，沙门氏菌菌株将表达融合到p24抗原上的p24抗原。 III型分泌蛋白，SipC，已知其直接易位 到宿主细胞的细胞质中 这种方法将使效率更高。 p24表位的I类呈递，否则将被 当p24作为可溶性细胞内抗原递送时，沙门氏菌抗原 抗原的 最后，研究人员将使用沙门氏菌疫苗株 结合这两种新方法来评估CTL诱导， 表达HLA-A2. 1和人CD8的双转基因小鼠系，以测试 这些疫苗引发适当免疫的潜在功效 人类的反应。 这些研究的结果可能会直接影响 应用于生产有效的疫苗， 调节免疫系统以产生针对HIV的保护性反应。