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：
9474682
负责人：
Lena Al-Harthi
金额：
$ 55.75万
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 2022-01-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9474682
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 Gene Targeting 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 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 cost humanized mouse in vivo insight migration motor impairment nervous system disorder 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：HIV引起一系列神经系统缺陷，称为HIV相关神经系统疾病（手）。即使在抗逆转录病毒疗法的联合，预计随着HIV+人口年龄的增长。对艾滋病毒如何入侵大脑和动手机制的基本了解知之甚少。在此应用中，我们将重点介绍CD4+ T细胞的作用和 CD4DIMCD8BRIGHT T细胞在HIV神经浸润，持久性和手中。 CD4DIMCD8BRIGHT T细胞是在其表面共表达CD4的CD8+ T细胞的独特子集。他们暴露了有力外周中的抗病毒反应。最近，我们表明CD8+ T细胞迁移到 HIV背景下的中枢神经系统在Wnt/ -catenin信号传导中引起CD4DIMCD8Bright T细胞 - 依赖方式。在大脑中，CD4DIMCD8Bright T细胞暴露了高潜力的抗HIV 回答。这种反应的结果是一方面控制艾滋病毒，但也许是诱导大脑注射和受伤的成本。基于我们出版的初步数据，我们假设，因为外围CD4DIMCD8BRIGHT T细胞容易受到HIV的影响感染，它们将有助于艾滋病毒神经入侵（AIM 1），但因为它们强烈表达 -catenin及其促生存的靶基因Bcl-XL感染的CD4DIMCD8BRIGHT T细胞将持续存在中枢神经系统作为艾滋病毒的水库（AIM 2）。此外，因为CD4DIMCD8Bright安装有效的反HIV 反应并过度激活，它们的频率将与CNS中较低的HIV含量相关但是，神经毒素的水平较高，神经认知性能较差（AIM 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（搜索）和美国军事艾滋病毒的研究合作研究计划（USMHRP）解决此中心假设。我们的学习将对HIV神经侵袭，HIV神经持久性和T细胞的作用建立新的理解在介导神经病发生/手的神经免疫轴中。这种理解可以提供用于改善和/或减少手的热干预的新方法，将提供对中枢神经系统中艾滋病毒持久性的有价值的见解。