Induction of Mucosal Cellular Immunity by HIV-1 Vaccine Vectors

描述（由候选人提供）：产生强效粘膜细胞免疫应答的能力是疫苗开发的一个重要目标。粘液免疫在HIV感染的情况下可能特别关键，这不仅是因为传播通常发生在粘膜表面，而且因为肠粘膜中的CD 4 + T淋巴细胞在疾病过程的早期优先被靶向破坏。然而，产生有效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引发环境和粘膜微环境塑造疫苗引起的粘膜细胞免疫应答的分子机制。我们假设，疫苗引起的细胞免疫记忆在粘膜表面的初始引发环境和随后的信号，动态重编程T淋巴细胞归巢特异性和表型的粘膜微环境的解剖和分子特性的形状。我们建议用以下三个具体目标来检验这一假设：1。确定全身接种疫苗后赋予CD 8 + T淋巴细胞粘膜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活化的CD 8 + T淋巴细胞的分化; 3.评估粘膜树突状细胞和视黄酸重编程疫苗诱导的CD 8 + T淋巴细胞归巢特异性的能力。 相关性：全世界有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，死于艾滋病并发症的人数也差不多。因此，迫切需要一种预防性的艾滋病毒疫苗。由于HIV传播通常发生在粘膜表面，并且病毒优先靶向粘膜CD 4 + T淋巴细胞进行破坏，因此非常需要产生有效粘膜免疫的疫苗。

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.