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.

科尔森，丹尼斯·L。 项目摘要 全球抗逆转录病毒疗法的HIV相关神经认知疾病（手）持续存在（〜30％的患病率） （ART）经过处理的个体，尽管严重的手（与HIV相关的痴呆症/HAN）大大减少了。 全身和中枢神经系统室中氧化应激的生物标志物与 手，即使在经过艺术治疗的个人中。最近，我们分析了大脑（> 150个NNTC供体）和 发现在患有氧化应激的关键酶调节剂中缺乏血红素氧酶-1（HO-1） 手。这种作用与艺术的使用无关，并且与脑巨噬细胞激活和I型相关 干扰素反应。我们进一步定义了通过 表明：i）单核细胞衍生巨噬细胞（MDM）的HIV感染一致，有选择地减少 HO-1表达并增加神经毒素（谷氨酸）释放； ii）已建立的HIV感染的艺术治疗 在MDM（HIV/MDM）中，不能阻止神经毒素释放，而iii）恢复HIV/MDM中HO-1表达 确实可以防止神经毒素释放，而与ART和HIV复制无关。我们的新初步研究 暗示通过常见的HO-1基因启动子序列变异对脑HO-1表达的失调 （GTN二核苷酸重复长度），并通过脑HO-1表达的区域变化 发病。此HO-1 GTN二核苷酸重复变化先前已与等离子体相关 HIV疾病进展的标志物（SCD14，HIV负载）和我们的大脑分析表明有很强的 HO-1启动子GTN重复长度与HIV脑炎的存在之间的相关性。另外，我们的 尸体猕猴的猕猴大脑（n = 18）的初步研究表现出一致的区域（9个区域） HO-1表达水平的大脑差异，在深脑结构中的水平最低，在人类中，艾滋病毒 影响特别深刻。因此，我们的研究确定了艾滋病毒驱动的脑HO-1缺乏症是主要的 手动发病机理的贡献者，他们表明HO-1启动子GTN重复变异和大脑 尽管使用了艺术，但区域HO-1变化仍可能是手的危险因素。我们假设HIV- 诱导的脑HO-1损失是有手的风险，HO-1启动子GTN重复变化不仅会影响 全身性艾滋病毒疾病进展，但也会导致疾病的进展和手。我们进一步假设 区域脑HO-1水平有助于选择性区域易受艾滋病毒损伤的脆弱性。我们将：1）确定 HO-1启动子GTN重复变异与HIV+受试者的神经认知之间的相关性（章程 患者队列）； 2）确定HO-1变异关联与隔室病理和HIV疾病标志物 （大脑，脾脏/NNTC尸检队列）； 3）定义巨噬细胞的神经病理体外反应， 星形胶质细胞，与血脑屏障功能相关的内皮细胞与HO-1调节和HO-的影响 1启动子GTN重复这些响应。这些研究可以为 评估对HO-1靶向疗法的细胞和临床反应。