Imaging the CNS SIV reservoir in a cART cessation model

项目摘要 目前有3800万艾滋病毒携带者(PLWH)，由于目前的进步结合在一起 抗逆转录病毒治疗(CART)，PLWH活得更长了。然而，由于潜在的病毒库，目前有 艾滋病毒无法治愈，因为病毒在停用CART后出现反弹。因此，已经投入了很大的努力 确定这一潜在的储藏库和根除战略。其中一个潜在的储备库是大脑，因为 在人类和非人类灵长类动物模型中都有证明。有趣的是，大脑潜在储存库可以重新播种 手推车停用后的周围器官。了解大脑在病毒反弹和定义中所起的作用 哪些细胞有助于CNS病毒逃逸是可行的治愈策略的关键。同样重要的是定义 CART下的神经炎性征象和CART停止后的变化为治疗提供信息 战略。在使用组合成像方法的应用中，我们将在 感染SIV的恒河猴停止CART后的大脑(目标1)，并使用多模式方法，我们将 明确SIV感染恒河猴在CART停止后的神经炎性特征(目标2)。我们 将使用3组感染SIV的恒河猴的脑组织，这些猕猴要么幼稚，要么在手推车上，要么 在CART停止后解决三个基本问题：1)哪种细胞类型(S)含有反弹病毒 在感染SIV的恒河猴中枢神经系统内CART停止后？2)这些细胞是否反弹 手推车停止后的病毒有复制能力的病毒吗？3)什么是神经炎性？ 与停用CART后中枢神经系统病毒反弹有关的签名？总的来说，我们的研究将使用 最先进的成像技术，更好地了解大脑作为病毒库的作用，为治愈提供信息 战略，以解决该保护区的独特特点。

Project Summary There are currently 38 million people living with HIV (PLWH) and due to current advances in combination antiretroviral therapy (cART), PLWH are living longer. However due to the latent viral reservoir, there is currently no cure for HIV as viral rebound arises following cART cessation. Therefore, a great effort has been put into defining this latent reservoir and strategies for eradication. One of these latent reservoirs is the brain, as demonstrated in both human and non-human primate models. Interestingly, brain latent reservoir can reseed peripheral organs following cART cessation. Understanding the role the brain plays in viral rebound and defining which cells contribute to CNS viral escape is critical for a viable cure strategy. Equally important is to define the neuroinflammatory signature under cART and changes following cART cessation to inform therapeutic strategies. In this application using a combinatorial imaging approach, we will define the viral reservoir in the brain after cART cessation in SIV-infected rhesus macaques (Aim 1) and using a multi-modal approach, we will define the neuroinflammatory signature in SIV-infected rhesus macaques following cART cessation (Aim 2). We will use brain tissue from 3 groups of SIV-infected rhesus macaques that are either cART naïve, on cART or following cART cessation to address three fundamental questions: 1) Which cell type(s) contain rebounding virus following cART cessation in the CNS of SIV-infected rhesus macaques? 2) Do these cells containing rebounding virus following cART cessation have replication competent virus? And 3) What is the neuroinflammatory signature associated with viral rebound in the CNS following cART cessation? Collectively our studies will use state-of-the art imaging technologies to better understand the role of the brain as a viral reservoir to inform cure strategies that addresses the unique characteristics of this sanctuary site.