Neuroimmune axis in HAND and HIV persistence in the brain

摘要：HIV导致一系列神经缺陷，称为HIV相关神经学 精神障碍(手)。手部是艾滋病毒的一种突出的共病状况，即使在 联合抗逆转录病毒疗法，预计将随着艾滋病毒人口的老龄化而增加。 对艾滋病毒如何侵入大脑和驱动手的机制有基本的了解 人们对此了解甚少。在本应用程序中，我们将重点介绍CD4T细胞和 CD4dimCD8亮T细胞在HIV神经侵袭、持久性和手部的作用CD4dimCD8亮T细胞 是CD8T细胞的一个独特的亚群，在其表面共同表达CD4。它们显示出强大的生命力 外周的抗病毒反应。最近，我们发现CD8T细胞迁移到 在艾滋病毒的背景下，中枢神经系统产生CD4dimCD8bright T细胞，在Wnt/-连环蛋白信号转导中- 依赖的态度。在大脑中，CD4dimCD8明亮的T细胞显示出强大的抗HIV能力 回应。这一反应的结果是一方面控制艾滋病毒，但可能在 导致脑部发炎和损伤的成本。基于我们发布的和初步的 数据，我们假设因为外周CD4dimCD8bright T细胞对HIV易感 感染，它们将促进艾滋病毒神经侵袭(目标1)，但因为它们强烈表达 -连环蛋白及其促生存靶基因Bclxl感染的CD4dimCD8bright T细胞将持续存在 将中枢神经系统作为艾滋病毒的宿主(目标2)。此外，因为CD4dimCD8bright安装了强大的抗HIV 反应和高度激活，它们的频率将与中枢神经系统中较低的HIV含量相关 但更高水平的神经炎症和更差的神经认知表现(目标3)。我们会 使用来自东南亚的体外、小动物研究和患者样本的组合 与夏威夷大学(SEARCH)和美国军方合作研究艾滋病毒 研究计划(USMHRP)来解决这一中心假设。总体而言，我们的研究将 重新认识HIV神经侵袭、HIV神经持续性和T细胞的作用 在神经免疫轴中介导神经发病机制/手。这种理解可以提供 治疗干预以改善和/或减少手的新方法，并将提供 对艾滋病毒在中枢神经系统中持续存在的有价值的见解。

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.