Induction of Mucosal Cellular Immunity by HIV-1 Vaccine Vectors

描述(由候选人提供)：产生有效的粘膜细胞免疫反应的能力是疫苗开发的一个重要目标。在艾滋病毒感染的背景下，粘膜免疫可能特别关键，不仅因为传播通常发生在粘膜表面，而且因为肠道粘膜中的CD4+T淋巴细胞在病程早期优先被破坏。然而，产生强大的粘膜细胞免疫所需的疫苗的具体特性尚不清楚。需要更好地理解淋巴细胞启动环境和粘膜微环境形成疫苗引起的粘膜细胞免疫反应的分子机制。我们假设疫苗在粘膜表面引起的细胞免疫记忆是由初始启动环境的解剖和分子特性以及来自粘膜微环境的后续信号形成的，这些微环境动态地重新编程T淋巴细胞归巢特异性和表型。我们建议通过以下三个具体目标来验证这一假说：1.确定系统免疫后赋予CD8+T淋巴细胞归巢能力的关键解剖学和分子事件；2.评估全身和粘膜微环境如何影响疫苗激活的CD8+T淋巴细胞的分化；3.评估粘膜树突状细胞和维甲酸重新编程疫苗诱导的CD8+T淋巴细胞归巢特异性的能力。 相关性：全球有4000多万人感染艾滋病毒。根据世界卫生组织最近的估计，每年有200多万人感染艾滋病毒，类似数量的人死于艾滋病并发症。因此，迫切需要一种预防性的艾滋病毒疫苗。由于艾滋病毒的传播通常发生在粘膜表面，并且病毒优先攻击粘膜中的CD4+T淋巴细胞以进行破坏，因此非常需要一种能够产生有效的粘膜免疫的疫苗。

DESCRIPTION (provided by candidate): The ability to generate potent mucosal cellular immune responses is an important goal of vaccine development. Mucosal immunity may be particularly critical in the setting of HIV infection, not only because transmission generally occurs at mucosal surfaces but because CD4+ T-lymphocytes in the intestinal mucosa are targeted preferentially for destruction early in the course of disease. However, the specific properties of a vaccine required to generate potent mucosal cellular immunity are not known. A better understanding is needed of the molecular mechanisms by which the lymphocyte priming milieu and mucosal microenvironments shape vaccine-elicited mucosal cellular immune responses. We hypothesize that vaccine-elicited cellular immune memory at mucosal surfaces is shaped both by the anatomic and molecular properties of the initial priming milieu and subsequent signals from mucosal microenvironments that dynamically reprogram T-lymphocyte homing specificity and phenotype. We propose to test this hypothesis with the following three Specific Aims: 1. To determine the key anatomic and molecular events that confer mucosal homing capacity on CD8+ T-lymphocytes following systemic vaccination; 2. To assess how systemic and mucosal microenvironments impact the differentiation of vaccine-activated CD8+ T-lymphocytes; 3. To evaluate the ability of mucosal dendritic cells and retinoic acid to reprogram the homing specificity of vaccine-elicited CD8+ T-lymphocytes. RELEVANCE: HIV infects over 40 million individuals worldwide. According to recent World Health Organization estimates, over 2 million people become infected with HIV each year and a similar number die from complications of AIDS. Therefore, a prophylactic HIV vaccine is urgently needed. Because HIV transmission generally occurs at mucosal surfaces and the virus preferentially targets mucosal CD4+ T- lymphocytes for destruction, a vaccine that generates effective mucosal immunity is highly desirable.