Neuroimmune axis in HAND and HIV persistence in the brain

翻译后摘要：艾滋病毒引起的神经功能缺损的频谱称为艾滋病毒相关的神经 疾病（手）。手是艾滋病毒的一个突出的共病条件，即使在时代， 联合抗逆转录病毒治疗，并预计将增加作为艾滋病毒+人口的年龄。 基本了解艾滋病毒如何侵入大脑和驱动手的机制 我们对此知之甚少。在本申请中，我们将重点关注CD 4 + T细胞的作用， CD 4dimCD 8bright T细胞在HIV神经侵袭、持久性和HAND中的作用CD 4dimCD 8bright T细胞 是CD 8 + T细胞的一个独特亚群，在其表面共表达CD 4。他们表现出强大的 外周的抗病毒反应。最近，我们发现CD 8 + T细胞迁移到 在HIV背景下，CNS在Wnt/β-连环蛋白信号传导中产生CD 4dimCD 8bright T细胞， 依赖的方式。在大脑中，CD 4dimCD 8bright T细胞表现出高度有效的抗HIV 应答这种反应的结果一方面是控制艾滋病毒， 引发炎症和大脑损伤的代价。根据我们公布的初步数据， 数据，我们假设，因为外周血CD 4dimCD 8bright T细胞对HIV易感， 感染，它们将有助于HIV神经侵袭（目的1），但由于它们强烈表达 β-连环蛋白及其促生存靶基因Bcl-XL感染的CD 4dimCD 8bright T细胞将持续存在， CNS作为HIV的储存库（目的2）。此外，由于CD 4dimCD 8bright安装有效的抗HIV 反应和过度活化，其频率将与CNS中较低的HIV含量相关 但神经炎症水平较高，神经认知能力较差（目的3）。我们将 使用体外、小动物研究和来自东南亚的患者样本的组合 与夏威夷大学（夏威夷大学）和美国军方艾滋病毒研究合作 研究计划（USMHRP），以解决这一核心假设。我们的研究将 建立对HIV神经侵袭、HIV神经持久性和T细胞作用的新认识 在神经免疫轴介导的神经发病机制/HAND。这种理解可以提供 用于改善和/或减少HAND的治疗干预的新方法，并将提供 对HIV在中枢神经系统中的持久性有价值的见解。

Abstract: HIV causes a spectrum of neurologic deficits known as HIV-Associated Neurologic Disorders (HAND). HAND is a prominent co-morbid condition of HIV even in the era of Combined Anti-Retroviral Therapy and is expected to increase as the HIV+ population ages. Fundamental understanding of how HIV invades the brain and mechanisms that drive HAND are poorly understood. In this application we will focus on the role of CD4+ T cells and CD4dimCD8bright T cells in HIV neuroinvasion, persistence, and HAND. CD4dimCD8bright T cells are a unique subset of CD8+ T cells that co-express CD4 on their surface. They exhibit potent anti-viral responses in the periphery. Recently, we showed that migration of CD8+ T cells into the CNS in context of HIV gives rise to CD4dimCD8bright T cells, in a Wnt/-catenin signaling - dependent manner. Within the brain, CD4dimCD8bright T cells exhibit highly potent anti-HIV responses. The consequence of this response is controlling HIV on one hand but perhaps at the cost of inducing inflammation and injury in the brain. Based on our published and preliminary data, we hypothesize that because peripheral CD4dimCD8bright T cells are susceptible to HIV infection, they will contribute to HIV neuroinvasion (Aim 1), yet because they robustly express -catenin and its pro-survival target gene, Bcl-XL, infected CD4dimCD8bright T cells will persist in the CNS as a reservoir for HIV (Aim 2). Further, because CD4dimCD8bright mount potent anti-HIV responses and are hyper-activated, their frequency will correlate with lower HIV content in CNS but higher level of neuroinflamamtion and worse neurocognitive performance (Aim 3). We will use a combination of in vitro, small animal studies, and patient samples from the Southeast Asia Research Collaboration with the University of Hawaii (SEARCH) and the US Military HIV Research Program (USMHRP) to address this central hypothesis. Collectively our studies will establish a new understanding of HIV neuroinvasion, HIV neuro-persistence, and role of T cells in the neuro-immune axis mediating neuropathogenesis/HAND. This understanding can provide new approaches for therapeutic intervention to ameliorate and/or reduce HAND and will provide valuable insights into HIV persistence in the CNS.