Regulation of Heme Oxygenase in HIV/HAND Pathogenesis

HIV/HAND 发病机制中血红素加氧酶的调节

基本信息

批准号：
9334937
负责人：
Dennis Larry Kolson
金额：
$ 55.97万
依托单位：
UNIVERSITY OF PENNSYLVANIA
依托单位国家：
美国
项目类别：
财政年份：
2016
资助国家：
美国
起止时间：
2016-08-18 至 2021-05-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9334937
关键词：
AIDS Dementia Complex Astrocytes Autopsy Biological Markers Blood - brain barrier anatomy Blood capillaries Brain Cell Culture Techniques Cells Central Nervous System Diseases Clinical DNA Dinucleotide Repeats Disease Marker Disease Progression Endothelial Cells Enzymes Functional disorder Genes Glutamates HIV HIV Infections HIV encephalitis HIV-associated neurocognitive disorder Heme Human Immune In Vitro Individual Inflammation Injury Interferon Type I Length Link Macaca mulatta Macrophage Activation Modeling National NeuroAids Tissue Consortium Neurocognition Neurocognitive Neurocognitive Deficit Neuronal Injury Neuropathogenesis Neurotoxins Oxidative Stress Oxygenases Pathogenesis Pathology Patients Plasma Prevalence Proteins Regulation Risk Risk Factors SHH gene Signal Pathway Specimen Spleen Structure Tissues Variant WNT Signaling Pathway antioxidant enzyme antiretroviral therapy biological adaptation to stress capillary cell motility cohort frontal lobe heme oxygenase-1 human tissue immune activation macrophage migration monocyte neurotoxicity prevent promoter response restoration targeted treatment

项目摘要

Kolson, Dennis L. Project Summary HIV associated neurocognitive disorders (HAND) persist (~30% prevalence) worldwide in antiretroviral therapy (ART)-treated individuals despite a profound reduction in severe HAND (HIV-associated dementia/HAD). Biomarkers of oxidative stress in both systemic and CNS body compartments are strongly correlated with HAND, even in ART-treated individuals. Recently, we analyzed autopsied brains (>150 NNTC donors) and found a deficiency of a critical enzyme modulator of oxidative stress, heme oxygenase-1 (HO-1,) in those with HAND. This effect was independent of ART use and it correlated with brain macrophage activation and type I interferon responses. We further defined a link between brain HO-1 deficiency and HIV neuropathogenesis by showing that: i) HIV infection of monocyte-derived macrophages (MDM) consistently and selectively reduces HO-1 expression and increases neurotoxin (glutamate) release; ii) ART treatment of established HIV infection in MDM (HIV/MDM) does not prevent neurotoxin release, while iii) restoration of HO-1 expression in HIV/MDM does prevent neurotoxin release independent of ART and HIV replication. Our new preliminary studies also implicate dysregulation of brain HO-1 expression through a common HO-1 gene promoter sequence variation (GTn dinucleotide repeat length) and through regional variation in brain HO-1 expression in HAND pathogenesis. This HO-1 GTn dinucleotide repeat variation has previously been correlated with plasma markers of HIV disease progression (sCD14, HIV load) and our brain analyses demonstrate a strong correlation between HO-1 promoter GTn repeat length and the presence of HIV encephalitis. Additionally, our preliminary studies of autopsied rhesus macaque brains (n=18) demonstrated consistent regional (9 regions) brain differences in HO-1 expression levels, with lowest levels in deep brain structures where, in humans, HIV effects are particularly profound. Thus, our studies identify HIV-driven brain HO-1 deficiency as a major contributor to HAND pathogenesis, and they suggest that HO-1 promoter GTn repeat variation and brain regional HO-1 variation could be risk factors for HAND despite the use of ART. We hypothesize that HIV- induced brain HO-1 loss is a risk for HAND and that HO-1 promoter GTn repeat variation influences not only systemic HIV disease progression but also CNS disease progression and HAND. We further hypothesize that regional brain HO-1 levels contribute to selective regional vulnerability to HIV injury. We will: 1) Determine the correlation between HO-1 promoter GTn repeat variation and neurocognition in HIV+ subjects (CHARTER patient cohort); 2) Identify HO-1 variation associations with compartmental pathology and HIV disease markers (brain, spleen/NNTC autopsy cohort); and 3) Define the neuropathological in vitro responses of macrophages, astrocytes, endothelial cells relevant for blood-brain barrier function to HO-1 modulation and effects of the HO- 1 promoter GTn repeat variation on these responses. These studies can provide critical information for assessing cellular and clinical responses to HO-1-targeted therapies.

科尔森，丹尼斯·L. 项目概要 HIV 相关神经认知障碍 (HAND) 在全球抗逆转录病毒治疗中持续存在（患病率约 30%）尽管严重的 HAND（HIV 相关痴呆/HAD）显着减少，但接受 ART 治疗的个体。全身和中枢神经系统身体区室中氧化应激的生物标志物与手，即使是在接受 ART 治疗的个体中。最近，我们分析了尸检大脑（> 150 名 NNTC 捐献者）并发现患有以下疾病的人缺乏氧化应激的关键酶调节剂血红素加氧酶-1 (HO-1) 手。这种效应与 ART 的使用无关，并且与脑巨噬细胞激活和 I 型巨噬细胞相关干扰素反应。我们通过以下方法进一步确定了大脑 HO-1 缺陷与 HIV 神经发病机制之间的联系：表明： i) 单核细胞衍生巨噬细胞 (MDM) 的 HIV 感染持续且选择性地减少 HO-1 表达并增加神经毒素（谷氨酸）释放； ii) 已确诊的 HIV 感染的 ART 治疗 MDM (HIV/MDM) 中的 HO-1 表达不会阻止神经毒素释放，而 iii) HIV/MDM 中 HO-1 表达的恢复确实可以防止神经毒素的释放，而与 ART 和 HIV 复制无关。我们新的初步研究还通过常见的 HO-1 基因启动子序列变异暗示大脑 HO-1 表达失调（GTn 二核苷酸重复长度）并通过 HAND 中大脑 HO-1 表达的区域变化发病。这种 HO-1 GTn 二核苷酸重复变异先前已与血浆相关 HIV 疾病进展的标志物（sCD14、HIV 载量）和我们的大脑分析表明， HO-1 启动子 GTn 重复长度与 HIV 脑炎的存在之间的相关性。此外，我们的对尸检恒河猴大脑（n=18）的初步研究表明，区域一致（9个区域） HO-1 表达水平的大脑差异，在人类的深部大脑结构中水平最低，其中 HIV 影响尤为深远。因此，我们的研究将 HIV 驱动的大脑 HO-1 缺陷确定为主要的 HAND 发病机制的贡献者，他们认为 HO-1 启动子 GTn 重复变异和大脑尽管使用了 ART，但区域性 HO-1 变异可能是 HAND 的危险因素。我们假设 HIV- 诱导的脑 HO-1 丢失是 HAND 的一个风险，HO-1 启动子 GTn 重复变异不仅影响全身性 HIV 疾病进展以及 CNS 疾病进展和 HAND。我们进一步假设大脑区域 HO-1 水平导致选择性区域易受 HIV 损伤。我们将： 1) 确定 HIV+ 受试者中 HO-1 启动子 GTn 重复变异与神经认知之间的相关性（CHARTER 患者队列）； 2) 确定 HO-1 变异与区室病理学和 HIV 疾病标志物的关联（脑、脾/NNTC 尸检队列）； 3) 定义巨噬细胞的神经病理学体外反应，星形胶质细胞、与血脑屏障功能相关的内皮细胞对 HO-1 的调节以及 HO-的影响 1 启动子 GTn 重复这些反应的变异。这些研究可以提供关键信息评估 HO-1 靶向治疗的细胞和临床反应。