Modulation of the early host response to SIV in pathogenic infection

描述（由申请人提供）：尽管有效的艾滋病疫苗是遏制全球艾滋病流行的最大希望，但默克公司t细胞疫苗的失败凸显了我们在疫苗保护相关知识方面的空白。目前，人们再次强调有必要对艾滋病的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。猿类免疫缺陷病毒（SIV）的自然宿主已经与该病毒共同进化了数百万年，并以一种不发生疾病进展或尽管持续病毒血症显着减缓的方式适应了SIV。了解使自然宿主无致病性的机制与艾滋病基础研究高度相关，并且可以将艾滋病疫苗研究的范围扩大到实现无菌保护的目标之外，以开发其他新的治疗策略。在最近的研究中，我们发现恒河猴（RM）感染SIV后的急性事件与自然宿主黑白鹅（SM）不同，CD4+ T淋巴细胞凋亡和TNF-受体相关凋亡诱导配体（TRAIL）的增加。我们假设TRAIL的增加导致CD4+ T淋巴细胞凋亡增加，启动旁观者T淋巴细胞活化，对慢性免疫的发展至关重要致病性慢病毒感染后的激活和艾滋病进展。在这项授权中，我们建议研究TRAIL的抑制是否会导致恒河猴SIV感染结果的改变。我们还建议使用表达SIV免疫原的基于单纯疱疹病毒（HSV）的疫苗方法，对SM和RM早期宿主对免疫原反应的差异进行详细检查。我们的具体目标是：具体目标#1：研究一种假设，即TRAIL的急性增加是致病性慢病毒感染的主要特征，并与诱导CD4+ T淋巴细胞凋亡和艾滋病的发展有因果关系。特异性目的2：确定在没有或存在SIV感染的情况下，黑白眉猴和恒河猴的CD4+ T淋巴细胞对trail介导的细胞凋亡的易感性是否存在差异。特异性目标#3：研究接种疫苗的黑白眉猴和恒河猴对SIV免疫原的早期先天和适应性宿主反应的差异。该项目的目标是更好地定义致病性和非致病性SIV感染的早期宿主对SIV反应的差异，目的是制定干预治疗策略，减轻疾病发展为艾滋病。将研究感染SIV和接种SIV疫苗的黑白脸猴和恒河猴对SIV的早期先天和适应性宿主反应的差异。

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.