Modulation of the early host response to SIV in pathogenic infection

描述（由申请人提供）：虽然有效的艾滋病疫苗是遏制全球艾滋病流行的最大希望，但基于T细胞的默克疫苗的失败突出了我们在疫苗保护相关知识方面的空白。目前，人们重新强调有必要对艾滋病致病机制进行更多的基础研究，并在非人灵长类动物模型中开发治疗策略。猴免疫缺陷病毒（SIV）的天然宿主与该病毒共同进化了数百万年，并适应了SIV，尽管存在持续的病毒血症，但疾病进展不会发生或显着减缓。了解机制，使非致病性的自然宿主是高度相关的基础艾滋病研究，可以扩大范围的艾滋病疫苗研究的目标以外，实现无菌保护，开发新的治疗策略。在最近的研究中，我们发现SIV感染恒河猴（RM）后的急性事件与自然宿主白眉猴（SM）中发生的事件不同，涉及CD 4 + T淋巴细胞凋亡的存在和TNF-受体相关的凋亡诱导配体（TRAIL）的增加。T淋巴细胞凋亡启动旁观者T淋巴细胞活化，并且在致病性慢病毒感染后慢性免疫活化和AIDS进展的发展中至关重要。在这项研究中，我们建议研究是否抑制TRAIL将导致SIV感染恒河猴的结果的改变。我们还建议进行一个详细的检查在SM和RM使用单纯疱疹病毒（HSV）为基础的疫苗表达SIV免疫原的方法在早期宿主对免疫原的反应的差异。我们的具体目标是：具体目标1：研究以下假设：TRAIL产生的急性增加是致病性慢病毒感染的主要特征，并与诱导CD 4 + T淋巴细胞凋亡和AIDS的发生有因果关系。具体目标#2：确定在SIV感染存在或不存在的情况下，白眉猴和恒河猴CD 4 + T淋巴细胞对TRAIL介导的凋亡的易感性是否不同。具体目标#3：研究接种疫苗的白眉猴和恒河猴对SIV免疫原的早期先天性和适应性宿主反应的差异。该项目的目标是更好地确定病原性和非病原性SIV感染中早期宿主对SIV反应的差异，目的是开发干预治疗策略，以减缓疾病向AIDS的进展。将在SIV感染和免疫的白眉猴和恒河猴中研究早期先天性和适应性宿主对SIV反应的差异。

DESCRIPTION (provided by applicant): Although an effective AIDS vaccine is the best hope for containing the world-wide AIDS epidemic, the failure of the T-cell-based Merck vaccine has highlighted our lacunae in knowledge about the correlates of vaccine protection. There is currently renewed emphasis on the necessity for more basic research on mechanisms of AIDS pathogenicity and development of therapeutic strategies in the nonhuman primate model. Natural hosts of the simian immunodeficiency virus (SIV) have co-evolved with the virus for millions of years and adapted to SIV in a way that disease progression does not occur or is markedly slowed down despite persistent viremia. Understanding mechanisms that allow nonpathogenicity in natural hosts is highly relevant for basic AIDS research and can expand the scope of AIDS vaccine research beyond the goal of achieving sterile protection, to developing additional novel therapeutic strategies. In recent studies we have shown that acute events following SIV infection in rhesus macaques (RM) differ from those occurring in the natural host sooty mangabeys (SM) with regards to the presence of CD4+ T lymphocyte apoptosis and increase in TNF- receptor associated apoptosis-inducing ligand (TRAIL) We hypothesize that increased TRAIL production leading to increased CD4+ T lymphocyte apoptosis initiates bystander T lymphocyte activation and is critical to the development of chronic immune activation and AIDS progression following pathogenic lentiviral infection. In this grant we propose to examine whether inhibition of TRAIL will result in alteration of the outcome of SIV infection in rhesus macaques. We also propose to perform a detailed examination of differences in the early host response to immunogens in SM and RM using a herpes simplex virus (HSV)-based vaccine approach expressing SIV immunogens. Our Specific Aims are: Specific Aim #1: Investigate the hypothesis that an acute increase in TRAIL production is a cardinal feature of pathogenic lentiviral infection and causally linked to induction of CD4+ T lymphocyte apoptosis and development of AIDS. Specific Aim #2: Determine whether sooty mangabey and rhesus macaque CD4+ T lymphocytes differ in their susceptibility to TRAIL-mediated apoptosis in the absence or presence of SIV infection. Specific Aim #3: Investigate differences in the early innate and adaptive host response to SIV immunogens in vaccinated sooty mangabeys and rhesus macaques. The goal of this project is to better define differences in the early host response to SIV in pathogenic and nonpathogenic SIV infection with the aim of developing interventional therapeutic strategies that attenuate disease progression to AIDS. Differences in the early innate and adaptive host response to SIV will be studied in SIV infected and vaccinated sooty mangabeys and rhesus macaques.