Regulation of Heme Oxygenase in HIV/HAND Pathogenesis

作者：John 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%患病率） （ART）治疗的个体，尽管严重HAND（HIV相关痴呆/HAD）显著减少。 全身和CNS体区室中氧化应激的生物标志物与 手，即使在艺术治疗的人。最近，我们分析了尸检的大脑（>150名NNTC供体）， 发现缺乏一种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，与脑巨噬细胞活化和I型胶原蛋白有关。 干扰素反应。我们进一步确定了脑HO-1缺乏和HIV神经发病机制之间的联系， 表明：i）单核细胞衍生的巨噬细胞（MDM）的HIV感染一致地和选择性地减少了 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ART治疗 在MDM（HIV/MDM）中的HO-1表达不能阻止神经毒素的释放，而iii）在HIV/MDM中HO-1表达的恢复 不依赖于ART和HIV复制而阻止神经毒素释放。我们新的初步研究还 HO-1基因启动子序列变异导致脑HO-1表达异常 (GTn二核苷酸重复长度）和通过HAND中脑HO-1表达的区域变化 发病机制这种HO-1 GTn二核苷酸重复变异以前与血浆 HIV疾病进展的标志物（sCD 14，HIV载量）和我们的大脑分析表明， HO-1启动子GTn重复序列长度与HIV脑炎的相关性。此外，我们的 对尸检的恒河猴脑（n=18）的初步研究表明一致的区域（9个区域） HO-1表达水平的脑差异，在人类中， 影响特别深远。因此，我们的研究将HIV驱动的脑HO-1缺乏确定为主要的 HAND发病机制的贡献者，他们认为HO-1启动子GTn重复变异和脑 尽管使用了抗逆转录病毒疗法，但区域HO-1变异可能是HAND的危险因素。 诱导的脑HO-1丢失是HAND的风险，HO-1启动子GTn重复序列变异不仅影响HAND， 系统性HIV疾病进展以及CNS疾病进展和HAND。我们进一步假设， 区域脑HO-1水平有助于选择性区域对HIV损伤的脆弱性。我们将：1）确定 HO-1启动子GTn重复序列变异与HIV阳性受试者神经认知功能的相关性（CHARTER 2）鉴定HO-1变异与房室病理学和HIV疾病标志物的关联 （脑、脾/NNTC尸检组群）;和3）定义巨噬细胞的神经病理学体外应答， 与血脑屏障功能相关的星形胶质细胞、内皮细胞对HO-1的调节以及HO-1的作用。 1启动子GTn重复变异对这些反应的影响。这些研究可以提供关键信息， 评估对HO-1靶向治疗的细胞和临床反应。

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.