Imaging the CNS SIV reservoir in a cART cessation model

项目摘要 目前有3800万人感染艾滋病毒（PLWH），由于目前的进步， 抗逆转录病毒治疗（cART），PLWH活得更长。然而，由于潜伏的病毒库，目前有 艾滋病毒无法治愈，因为停止cART后会出现病毒反弹。因此，已经投入了很大的努力， 定义这个潜在的储存库和根除策略。其中一个潜在的储存库是大脑， 在人类和非人类灵长类动物模型中均得到证实。有趣的是，大脑潜在的储存库可以重新播种 cART停止后的外周器官。了解大脑在病毒反弹中的作用， 哪些细胞有助于CNS病毒逃逸对于可行的治愈策略至关重要。同样重要的是， cART下的神经炎症特征和cART停止后的变化，以告知治疗 战略布局在使用组合成像方法的本申请中，我们将定义病毒库中的病毒库。 SIV感染恒河猴cART停止后的大脑（目的1），并使用多模式方法，我们将 定义cART停止后SIV感染的恒河猴中的神经炎症特征（Aim 2）。我们 将使用来自3组SIV感染的恒河猴的脑组织，这些恒河猴是cART初治的，正在接受cART的， 在cART停止后，解决三个基本问题：1）哪些细胞类型含有反弹病毒 在SIV感染的恒河猴的CNS中停止cART后，2)这些包含反弹的细胞 cART停止后的病毒是否具有复制能力？3）什么是神经炎症 与cART停止后CNS中病毒反弹相关的特征？我们的研究将使用 最先进的成像技术，以更好地了解大脑作为病毒储存库的作用， 解决这个避难所的独特性的策略。

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.