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Neuroimmune axis in HAND and HIV persistence in the brain

HAND 中的神经免疫轴和大脑中的 HIV 持续存在

基本信息

批准号：
10088477
负责人：
Lena Al-Harthi
金额：
$ 55.13万
依托单位：
RUSH UNIVERSITY MEDICAL CENTER
依托单位国家：
美国
项目类别：
财政年份：
2017
资助国家：
美国
起止时间：
2017-04-20 至 2023-01-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10088477
关键词：
Accreditation Address Age Animal Model Animals Antiviral Response Astrocytes Automobile Driving Autopsy Blood Brain Brain Injuries CD4 Positive T Lymphocytes CD8-Positive T-Lymphocytes CD8B1 gene Cells Chronic Clinical Clinical Research Collaborations Data Environment Exhibits Frequencies Genes Genetic Transcription HIV HIV Infections HIV-associated neurocognitive disorder Hawaii Human Immune In Vitro Individual Infection Inflammation Inflammatory Response Injury Invaded Ligands Mediating Mediator of activation protein Military Personnel Modeling Mus Nervous System Trauma Neurocognitive Neurocognitive Deficit Neuroimmune Neurologic Deficit Neuronal Injury Neuropathogenesis Outcome Participant Pathogenicity Pathway interactions Patients Performance Peripheral Peripheral Blood Mononuclear Cell Ploidies Population Publishing Research Research Personnel Role SIV Sampling Signal Transduction Site Source Southeastern Asia Surface Surveys T cell response T-Lymphocyte T-Lymphocyte Subsets Testing Therapeutic Intervention Universities Viral Virus antimicrobial antiretroviral therapy base beta catenin comorbidity cost humanized mouse in vivo insight migration motor impairment nervous system disorder neuroAIDS neuroinflammation novel novel therapeutic intervention programs reconstitution response

项目摘要

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.

摘要：艾滋病毒引起一系列神经系统缺陷，称为艾滋病毒相关神经系统缺陷。疾病（手）。即使在当今时代，手部疾病也是艾滋病毒的一种突出共病。联合抗逆转录病毒疗法预计会随着 HIV+ 人口老龄化而增加。对 HIV 如何侵入大脑以及驱动 HAND 的机制有基本了解人们了解甚少。在此应用中，我们将重点关注 CD4+ T 细胞的作用和 CD4dimCD8bright T 细胞在 HIV 神经侵袭、持续性和 HAND 中的作用。 CD4dimCD8bright T 细胞是 CD8+ T 细胞的一个独特子集，在其表面共表达 CD4。他们表现出强大的外周的抗病毒反应。最近，我们发现 CD8+ T 细胞迁移到 HIV 背景下的中枢神经系统在 Wnt/-连环蛋白信号传导中产生 CD4dimCD8bright T 细胞 - 依赖方式。在大脑内，CD4dimCD8bright T 细胞表现出高效的抗 HIV 能力回应。这种反应的结果是一方面控制了艾滋病毒，但也许另一方面诱发大脑炎症和损伤的成本。根据我们已发布的和初步的根据数据，我们假设由于外周 CD4dimCD8bright T 细胞容易感染 HIV 感染后，它们会导致 HIV 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 Bcl-XL，感染的 CD4dimCD8bright T 细胞将持续存在中枢神经系统作为 HIV 的储存库（目标 2）。此外，由于 CD4dimCD8bright 具有有效的抗 HIV 作用反应并且过度激活，其频率将与中枢神经系统中较低的 HIV 含量相关但神经炎症水平更高，神经认知能力更差（目标 3）。我们将结合体外、小动物研究和来自东南亚的患者样本与夏威夷大学 (SEARCH) 和美国军方艾滋病毒研究合作研究计划（USMHRP）旨在解决这一中心假设。总的来说，我们的研究将对 HIV 神经侵袭、HIV 神经持久性和 T 细胞的作用建立新的认识在介导神经发病机制/HAND 的神经免疫轴中。这种理解可以提供改善和/或减少 HAND 的治疗干预新方法将提供关于艾滋病毒在中枢神经系统中持续存在的宝贵见解。