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 全球HIV-1感染。 人们认为抗HIV-1免疫力 在粘膜部位将减少这种传播，从而减少 有助于保护免受感染。 有几种方法 可以通过其中诱导粘膜免疫，特别是某些 细菌毒素已被证明是有效的粘膜佐剂。 这 提案旨在利用这些佐剂来诱导保护 猕猴中的SIV/HIV-1重组（SHIVS）的粘膜挑战。 最初是最佳粘膜佐剂和最有效的 将选择挑战病毒，随后粘膜免疫将 使用选定的佐剂和这种免疫力在猕猴中诱导 然后将测试其能够赋予粘膜保护的能力 以及选定的SHIVS的系统性挑战。 下列 问题将被解决。 1）HIV-1的体外生物学特性可预测体外 用HIV-1信封基因构建的SHIV的特性，并做到这一点 预测能力扩展到体内特性，例如跨越传输 粘膜表面？ 2）可以使用大肠带热肠毒素（LT）的无毒突变体 在小鼠中诱导抗HIV粘膜免疫，是突变体LT（R192G）A 优质粘膜佐剂？ 3）是全身启动的一种方案，然后是粘膜促进 诱导粘膜免疫的卓越方法？ 4）重复粘膜免疫的方案可以诱导保护 粘膜感染，甚至来自全身感染？ 这些问题的答案最终将确定是否粘膜 使用HIV-1抗原和LT的非氧化突变体对人类进行免疫接种 可以提供免受HIV-1感染的保护