Oxidative Stress, Immune Activation, and Therapeutic Targeting in HIV/HAND

HIV/HAND 中的氧化应激、免疫激活和治疗靶向

基本信息

批准号：
8732299
负责人：
Dennis Larry Kolson
金额：
$ 54.82万
依托单位：
UNIVERSITY OF PENNSYLVANIA
依托单位国家：
美国
项目类别：
财政年份：
2014
资助国家：
美国
起止时间：
2014-05-06 至 2019-04-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8732299
关键词：
AIDS prevention Animals Antioxidants Autopsy Biological Markers Brain CD8B1 gene Cells Cellular Infiltration Central Nervous System Diseases Clinical Clinical Trials Data Disease Disease Progression Enrollment Enzymes Executive Dysfunction FDA approved Fumarates Functional disorder Glutamates HIV HIV Infections HIV therapy HIV-1 Hand Human Immune In Vitro Individual Infection Inflammation Label Link Macaca Macaca mulatta Macrophage Activation Mediating Messenger RNA Modeling Multiple Sclerosis National NeuroAids Tissue Consortium Nerve Degeneration Neurocognitive Neuropathogenesis Neuroprotective Agents Neurotoxins Outcome Oxidative Stress Pathogenesis Pathway interactions Patients Performance Peripheral Blood Mononuclear Cell Pharmaceutical Preparations Pilot Projects Plasma Prefrontal Cortex Primates Proteins Regimen SIV Specimen Therapeutic Tissues Ubiquitination Validation Viral Load result Virus Diseases antiretroviral therapy base biological adaptation to stress brain tissue cohort disorder prevention experience frontal lobe heme oxygenase-1 immune activation improved in vitro Model mRNA Stability macrophage monocyte neuroinflammation neuroprotection neurotoxicity new therapeutic target prevent protein degradation protein expression public health relevance response success therapeutic target trafficking treatment effect

项目摘要

DESCRIPTION: HIV associated neurocognitive disorders (HAND) remain prevalent (~50%) despite remarkably improved patient survival due to improved antiretroviral therapy (ART) regimens. In HAND, CNS neuroinflammation & oxidative stress persist despite ART and continue to contribute to neuropathogenesis, which emphasizes the critical need for identifying host targets for adjunctive therapy for HAND prevention. We recently identified the cellular detoxifying/antioxidant enzyme, heme oxygenase-1 (HO-1), as such a target and we have demonstrated a significant deficiency of HO-1 expression in brain tissue from individuals with HAND. We also identified the recently FDA-approved CNS-penetrating multiple sclerosis drug (dimethyl fumarate/DMF/Tecfidera(R)), which stimulates HO-1 expression, as a unique candidate neuroprotectant for prevention of HAND. We propose to define the association between brain HIV-1 infection, HO-1 expression and HAND, and to establish a proof-of-concept therapeutic link to HO-1 induction as an adjunctive approach for HAND neuroprotection in a pilot dimethyl fumarate/DMF-treatment study of SIV-infected macques. Using our in vitro HIV neurodegeneration model we showed that HO-1 acts as a specific suppressor of HIV- induced neurodegeneration and that dimethyl fumarate/DMF induction of HO-1 is highly neuroprotective. Through analysis of autopsied brain tissue specimens (dorsolateral frontal cortex) from more than 150 HIV+ individuals, we found a significant deficiency of HO-1 expression and showed that this HO-1 deficiency correlates with neurocognitive (executive) dysfunction. Thus, HO-1 brain deficiency is directly linked with neurocognitive dysfunction in HIV-infected individuals, and a therapeutic approach that potentially can correct this deficiency and improve neurocognitive outcomes is at hand. We hypothesize that HIV-mediated suppression of brain HO-1 expression contributes to neuropathogenesis of HAND and that induction of HO-1 expression with dimethyl fumarate/DMF in ART-treated HIV+ individuals can limit the neuroinflammation, neurodegeneration and neurocognitive decline associated with HAND. We will determine: 1) correlations between regional brain HO-1 expression, immune activation, viral load, and neurocognitive performance in HIV+ individuals~ 2) mechanisms of HO-1 dysregulation by HIV~ and 3) whether DMF treatment alters HO-1 expression, neuroimmune activation, and neuropathogenesis of brain SIV infection in macaques.

描述：HIV相关的神经认知障碍（手）仍然普遍存在（〜50％），尽管由于改善的抗逆转录病毒治疗（ART）方案，患者生存率明显提高。在手头，尽管有艺术，但中枢神经系统神经炎症和氧化应激仍然存在，并继续促进神经发病，这强调了识别宿主靶标的辅助治疗以预防手动治疗的关键需求。我们最近确定了细胞排毒/抗氧化剂酶，血红素加氧酶-1（HO-1），因为一个靶标，我们已经证明了有手的人在脑组织中表现出明显的HO-1表达缺陷。我们还确定了最近经FDA批准的CNS渗透多发性硬化症药物（富马酸二甲基/DMF/Tecfidera（R）），该药物刺激HO-1表达是一种独特的候选神经保护剂，可预防手。我们建议定义脑HIV-1感染，HO-1表达和手之间的关联，并建立与HO-1诱导的概念验证治疗链接，作为在富马酸二甲基二甲基/DMF型二甲基二甲基甲酸二甲基甲酸二甲基甲酸二甲基甲酸二甲基甲酸二甲基甲酸二甲基甲酸二甲基甲酸二甲基甲酸酯研究中的辅助方法。使用我们的体外HIV神经变性模型，我们表明HO-1充当HIV诱导的神经变性的特定抑制剂，HO-1的二甲基富马酸二甲基/DMF诱导HO-1具有高度神经保护性。通过分析150多个HIV+个体的载载脑组织标本（背外侧额叶皮层），我们发现了HO-1表达的显着缺陷，并表明此HO-1 缺乏症与神经认知（执行）功能障碍相关。因此，HO-1脑缺乏症与HIV感染者的神经认知功能障碍直接相关，并且可能可以纠正这种缺乏并改善神经认知结果的治疗方法即将到来。我们假设艾滋病毒介导的脑HO-1表达抑制有助于手动神经病发生，并且在ART治疗的HIV+个体中，HO-1表达用二甲基富马酸二甲基/DMF诱导可以限制神经炎症，神经变性，神经变性和神经认知的下降。我们将确定：1）HIV+个体中区域脑HO-HO-1表达，免疫激活，病毒载荷和神经认知性能之间的相关性〜2）HO-1通过HIV〜和3）HO-1失调的机制和3）DMF治疗是否可以改变HO-1的表达，神经免疫性激活和脑siv脑的神经病毒的神经病毒性脑库中的神经性神经病变。