NKT cells as modulators of AIDS vaccine efficacy

描述(申请人提供)：艾滋病流行30年来，全世界估计有3400万艾滋病毒感染者，其中近70%居住在撒哈拉以南非洲。尽管开发艾滋病疫苗的密集研究仍在继续，但到目前为止还没有出现有效的艾滋病毒疫苗。要使HIV疫苗成功，人们普遍认为它应该能够诱导粘膜免疫，诱导有效的细胞溶解和多功能的HIV特异性T细胞反应，以及具有广泛的中和活性和抗体依赖的细胞毒性(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器，可以决定全身和粘膜部位病原体特异性免疫反应的大小、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，具有强大的免疫调节特性，可以影响T细胞和B细胞的免疫。在这项拨款申请中，我们建议使用SIV感染猕猴模型来研究NKT激活将提高疫苗的免疫原性和改善疫苗对SIV感染的获得和控制的介导性保护这一假设。相反，缺乏NKT细胞可能会降低保护性减毒活SIV(LASIV)疫苗的效力。我们的具体目标是：#1.确定NKT耗竭单抗和NKT激活单抗的最佳体内给药方案，并研究它们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Prime-Boost重组AD26/Ad5-SIV疫苗方案的保护效果的假设。#3.研究假设，在NKT耗尽的情况下接种疫苗将消除高度保护性LASIV疫苗的保护效力。

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.