Maximizing CD8 T Cells for Protection

描述(由申请人提供) 摘要：艾滋病毒已经夺走了2500万人的生命。二十年的研究，但没有疫苗。从理论上讲，在依赖抗体的传统中和疫苗失败的地方，CD8T细胞免疫的产生可能会成功。但是，在经历了严峻的挑战后，新生的努力始终未能预防猴子的慢性SIV感染，第一次人类艾滋病毒CD8 T细胞疫苗试验完全失败。为什么？像许多人现在所说的那样，预防性CD8 T细胞疫苗是不可能的吗？我们假设，过去的努力由于安全第一的方法和对记忆CD8 T细胞数量、质量和保护位置的重要性的相对忽视而受挫。目前的方法在很大程度上是对过去失败的改进。早就应该采取更大胆的方法，至少在安全要求不那么严格的动物模型中是这样。如果SIV特异性记忆CD8 T细胞的数量是目前疫苗接种策略所确定的数量的500倍，那么它们能完成什么？如果这些细胞优先位于病毒进入的共同入口，并在接触后迅速破坏受感染的宿主组织，会发生什么？如果一种疫苗将大多数CD8 T细胞转化为HIV或SIV特异性记忆细胞，它们能否完全保护宿主并完全消除感染？或者，即使在理想的情况下，CD8 T细胞也无法实现这一目标？这项提案将回答这些基本问题。此外，它还将测试记忆性CD8T细胞生成的极限，并确定CD8T细胞保护的相关因素。如果成功，这项研究可能会证明预防性艾滋病毒疫苗在理论上是可能的。 公共卫生相关性：这项建议将调查记忆CD8 T细胞是如何通过接种产生的，并确定记忆CD8 T细胞数量、质量和位置之间的关系以及它们对预防感染的作用。这些发现将与疫苗接种和建立CD8T细胞依赖的保护性免疫的相关性直接相关。

DESCRIPTION (Provided by the applicant) Abstract: HIV has claimed >25 million lives. Two decades of research, but no vaccine. Theoretically, generation of CD8 T cell immunity may succeed where traditional, neutralizing antibody-dependent, vaccines have failed. But, nascent efforts have consistently failed to prevent chronic SIV infection in monkeys following a stringent challenge, and the first human HIV CD8 T cell vaccine trial was a complete failure. Why? Is a preventative CD8 T cell vaccine impossible, as many now suggest? We hypothesize that past efforts have been crippled by a safety-first approach and relative ignorance of the importance of memory CD8 T cell quantity, quality, and location to protection. Current approaches are largely refinements of past failures. A bolder approach is long overdue, at least in animal models where safety requirements are less stringent. What could SIV specific memory CD8 T cells accomplish if they were 500-fold more plentiful than what is established by current vaccination strategies? What if these cells were preferentially located at common portals of viral entry and destroyed infected host tissue quickly upon contact? If a vaccine converted most CD8 T cells into HIV or SIV specific memory cells, could they fully protect the host and eliminate the infection completely? Or are CD8 T cells incapable of fulfilling this goal, even under ideal scenarios? This proposal will answer these essential questions. Moreover, it will test the limits of memory CD8 T cell generation, and define CD8 T cell correlates of protection. If successful, this study may demonstrate that a preventative HIV vaccine is theoretically possible. Public Health Relevance: This proposal will investigate how memory CD8 T cells are generated via vaccination, and determine the relationship between memory CD8 T cell quantity, quality, and location and their contribution to protection from infection. These findings will have direct relevance to vaccination and to establishing correlates of CD8 T cell dependent protective immunity.