NKT cells as modulators of AIDS vaccine efficacy

描述（由申请人提供）：艾滋病流行三十年来，全球估计有3400万艾滋病毒感染者，近70%居住在撒哈拉以南非洲。 虽然正在继续进行开发艾滋病疫苗的密集研究，但目前还没有有效的艾滋病毒疫苗。对于成功的HIV疫苗，广泛接受的是它应该能够诱导粘膜免疫，引发有效的细胞溶解和多功能HIV特异性T细胞应答，沿着具有广泛定向中和活性和抗体依赖性细胞毒性（ADCC）活性的抗HIV抗体。先天免疫系统是适应性免疫的重要调节剂，并且可以在全身和粘膜部位形成病原体特异性免疫应答的幅度、质量和持久性。 自然杀伤T（NKT）细胞是先天免疫系统中独特的T细胞，具有可影响T和B细胞免疫的有效免疫调节特性。在这项资助申请中，我们建议使用SIV感染猕猴模型来研究NKT激活将改善疫苗免疫原性并改善疫苗介导的对SIV感染的获得和控制的保护的假设。相反，NKT细胞的缺乏可能会降低保护性减毒SIV活疫苗（LASIV）的效力。我们的目标是：#1。确定NKT消耗和NKT激活mAb体内给药的最佳给药方案，并表征其在食蟹猴血液和组织中的作用。#2.研究NKT激活的佐剂效应将增强异源初免-加强免疫重组Ad 26/Ad 5-SIV疫苗方案的保护效力的假设。#3.研究在NKT耗竭的情况下接种疫苗将废除高度保护性LASIV疫苗的保护效力的假设。

DESCRIPTION (provided by applicant): Thirty years into the AIDS epidemic, there are an estimated 34 million HIV-infected people worldwide and almost 70% reside in sub-Saharan Africa. Although intensive research towards developing an AIDS vaccine is continuing, there are as yet no effective HIV vaccines on the horizon. For a HIV vaccine to be successful, it is widely accepted that it should be able to induce mucosal immunity, elicit an effective cytolytic and polyfunctional HIV-specific T cell response along with anti-HIV antibodies that have broadly directed neutralization activity and antibody dependent cellular cytotoxicity (ADCC) activity. The innate immune system is an important modulator of adaptive immunity and can shape the magnitude, quality, and durability of pathogen-specific immune responses at systemic and mucosal sites. Natural killer T (NKT) cells are unique T cells of the innate immune system with potent immunoregulatory properties that can impact T and B cell immunity. In this grant application we propose to use the SIV infection macaque model to investigate the hypothesis that NKT activation will improve vaccine immunogenicity and improve vaccine-mediated protection against acquisition and control of SIV infection. Conversely, the absence of NKT cells may reduce the efficacy of a protective live attenuated SIV (LASIV) vaccine. Our specific aims are: #1. Determine the optimal dosing regimen for in vivo administration of the NKT-depleting and NKT-activating mAbs and characterize their effect in blood and tissues of cynomolgus macaques. #2. Investigate the hypothesis that the adjuvant effect of NKT activation will enhance the protective efficacy of a heterologous prime-boost recombinant Ad26/Ad5-SIV vaccine regimen. #3. Investigate the hypothesis that vaccination in the setting of NKT depletion will abrogate the protective efficacy of a highly protective LASIV vaccine.