MUCOSAL IMMUNITY AND PROTECTION

粘膜免疫和保护

• 批准号: 6299489
• 负责人: MARNIX L BOSCH
• 金额: $ 34.34万
• 依托单位: UNIVERSITY OF WASHINGTON
• 依托单位国家: 美国
• 财政年份: 2000
• 资助国家: 美国
• 起止时间: 2000-01-01 至 2000-12-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6299489
• 关键词: AIDS vaccines; Escherichia coli; HIV envelope protein; HIV envelope protein gp160; HIV infections; Macaca nemestrina; bacterial antigens; cell mediated lymphocytolysis test; enterotoxins; enzyme linked immunosorbent assay; flow cytometry; human immunodeficiency virus 1; humoral immunity; immunomodulators; laboratory mouse; live vaccine; mucosal immunity; nonhuman therapy evaluation; postmortem; recombinant proteins; recombinant virus; simian immunodeficiency virus; transcytosis; vaccinia virus; vector vaccine; virus antigen

Transmission through mucosal surfaces constitutes the major route of infection with HIV-1 worldwide. It is thought that anti-HIV-1 immunity at the mucosal sites will reduce such transmission and thereby contribute to protection from infection. There are several methods through which mucosal immunity can be induced and specifically some bacterial toxins have been shown to be potent mucosal adjuvants. This proposal aims at exploiting these adjuvants to induce protection from mucosal challenge with SIV/HIV-1 recombinants (SHIVs) in macaques. Initially the optimal mucosal adjuvant as well as the most potent challenge virus will be selected, and subsequently mucosal immunity will be induced in macaques using the selected adjuvant and this immunity will then be tested for it's ability to confer protection from mucosal and systemic challenges with the selected SHIVs. The following questions will be addressed. 1) Are in vitro biological properties of HIV-1 predictive for in vitro properties of SHIVs constructed with HIV-1 envelope genes, and does this predictive power extend to in vivo properties like transmission across mucosal surfaces? 2) Can nontoxic mutants of E. coli heat-labile enterotoxin (LT) be used to induce anti-HIV mucosal immunity in mice and is mutant LT(R192G) a superior mucosal adjuvant? 3)Is a regimen of systemic priming followed by mucosal boosting a superior method to induce mucosal immunity? 4) Can a regimen of repeated mucosal immunization induce protection from mucosal infection or even from systemic infection? The answers to these questions will ultimately determine whether mucosal immunization of humans using HIV-1 antigens and nonoxic mutants of LT can provide protection from HIV-1 infection

通过粘膜表面的传播构成了感染的主要途径。 全球HIV-1感染 据认为，抗HIV-1免疫力 将减少这种传播 有助于保护免受感染。 有几种方法 通过其可以诱导粘膜免疫， 细菌毒素已被证明是有效的粘膜佐剂。 这 一项提案旨在利用这些佐剂来诱导保护， 在猕猴中用SIV/HIV-1重组体（SHIV）进行粘膜攻击。 最初，最佳的粘膜佐剂以及最有效的 将选择攻击病毒，随后粘膜免疫将 使用所选佐剂在猕猴中诱导， 然后将测试其保护粘膜免受 和系统性的挑战。 以下 问题将得到解决。 1)HIV-1的体外生物学特性是否可预测体外 用HIV-1包膜基因构建的SHIV的特性， 预测能力扩展到体内特性，如跨 粘膜表面？ 2)E.大肠杆菌不耐热肠毒素（LT） 在小鼠中诱导抗HIV粘膜免疫，并且是突变LT（R192 G）a 上级粘膜佐剂？ 3）全身性引发随后粘膜加强的方案是否是一种有效的预防方法， 诱导粘膜免疫的上级方法？ 4)重复粘膜免疫方案是否能诱导 粘膜感染还是全身感染？ 这些问题的答案将最终决定是否粘膜 使用HIV-1抗原和LT的无氧突变体对人进行免疫 可以提供保护免受HIV-1感染