Regulation of Heme Oxygenase in HIV/HAND Pathogenesis

HIV/HAND 发病机制中血红素加氧酶的调节

• 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
• 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

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.

作者声明：Dennis L. 项目摘要 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(约30%) (抗逆转录病毒药物)治疗的个人，尽管严重手部疾病(艾滋病毒相关性痴呆症/HAD)大幅减少。 全身和中枢神经系统中氧化应激的生物标记物与 手，即使是接受过艺术治疗的人也是如此。最近，我们分析了尸检的大脑(&gt；150名NNTC捐赠者)和 发现氧化应激的关键酶调节剂--血红素加氧酶-1(HO-1)缺乏 手。这种作用与抗逆转录病毒药物的使用无关，并与脑巨噬细胞活化和I型有关。 干扰素反应。我们进一步确定了脑HO-1缺陷与HIV神经发病机制之间的联系 表明：i)单核细胞来源的巨噬细胞(MDM)的艾滋病毒感染持续和选择性地减少 HO-1的表达和增加神经毒素(谷氨酸)的释放；ii)ART治疗已确定的艾滋病毒感染 在MDM(HIV/MDM)中并不阻止神经毒素的释放，而III)在HIV/MDM中恢复HO-1的表达 确实可以防止神经毒素的释放，独立于抗逆转录病毒药物和艾滋病毒复制。我们新的初步研究也 共同的HO-1基因启动子序列变异与脑HO-1表达异常有关 (GTN二核苷酸重复长度)和通过HO-1在脑中表达的区域差异 发病机制。这种HO-1GTN二核苷酸重复变异以前曾与血浆相关 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脑炎的相关性此外，我们的 对恒河猴身体脑的初步研究(n=18)显示了一致的区域(9个区域)。 HO-1表达水平的大脑差异，在人类HIV感染的大脑深层结构中表达水平最低 其影响尤为深远。因此，我们的研究确定艾滋病毒驱动的大脑HO-1缺陷是一个主要的 HO-1启动子GTN重复变异与脑 尽管使用了抗逆转录病毒疗法，区域HO-1变异仍可能是HAND的危险因素。我们假设HIV病毒- 诱导性脑HO-1丢失是手部的风险，HO-1启动子GTN重复变异不仅影响 系统性HIV疾病的进展，也是中枢神经系统疾病的进展和手部。我们进一步假设 区域脑HO-1水平有助于对艾滋病毒损伤的选择性区域易感性。我们将：1)确定 HO-1启动子GTN重复变异与HIV+患者神经认知功能的相关性(英文) 患者队列)；2)确定HO-1变异与间隔病理和HIV疾病标志物的关系 (脑、脾/NNTC尸检队列)；以及3)定义巨噬细胞的体外神经病理反应， 与血脑屏障功能相关的星形胶质细胞、内皮细胞对HO-1的调控及HO-1的作用 1启动子GTN重复变异对这些反应的影响。这些研究可以为 评估HO-1靶向治疗的细胞和临床反应。