Modulation of the early host response to SIV in pathogenic infection

虽然有效的艾滋病疫苗是控制艾滋病在世界范围内流行的最大希望， 基于T细胞的默克疫苗的失败突出了我们在知识上的空白， 疫苗保护。目前，人们重新强调有必要对以下方面进行更多的基础研究： 艾滋病的致病机制和非人灵长类动物模型的治疗策略的发展。 猴免疫缺陷病毒（SIV）的自然宿主与该病毒共同进化了数百万年 并适应SIV的方式，疾病进展不会发生或显着减缓，尽管 持续性病毒血症了解机制，使非致病性在自然宿主是高度相关的 为基础的艾滋病研究，并可以扩大艾滋病疫苗的研究范围以外的目标，实现 无菌保护，开发其他新的治疗策略。最近的研究表明， 恒河猴（RM）感染SIV后的急性事件不同于自然宿主中发生的事件 白眉猴（SM）在CD 4 + T淋巴细胞凋亡和TNF-α增加的存在下， 受体相关凋亡诱导配体（TRAIL）我们假设增加TRAIL的产生， 导致增加的CD 4 + T淋巴细胞凋亡启动旁观者T淋巴细胞活化，并且对于 慢性免疫激活的发展和病原性慢病毒感染后的艾滋病进展。 在这项资助中，我们建议研究抑制TRAIL是否会导致SIV结局的改变 感染恒河猴。我们还建议在早期对差异进行详细检查， 使用单纯疱疹病毒（HSV）疫苗方法在SM和RM中对免疫原的宿主应答 表达SIV免疫原。我们的具体目标是：具体目标#1：调查假设， TRAIL产生的急剧增加是致病性慢病毒感染的主要特征，并且与以下疾病的发生有因果关系： 诱导CD 4 + T淋巴细胞凋亡与艾滋病发生具体目标#2：确定 白眉猴和恒河猴CD 4 + T淋巴细胞对TRAIL介导的细胞凋亡的易感性不同 在SIV感染的存在或不存在下的细胞凋亡。具体目标#3：研究早期 免疫白眉猴和恒河猴对SIV免疫原的先天性和适应性宿主应答。

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.