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

• 批准号: 8846141
• 负责人: Dennis Larry Kolson
• 金额: $ 51.95万
• 依托单位: UNIVERSITY OF PENNSYLVANIA
• 依托单位国家: 美国
• 财政年份: 2014
• 资助国家: 美国
• 起止时间: 2014-05-06 至 2019-01-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8846141
• 关键词: Animals; Antioxidants; Autopsy; Biological Markers; Brain; CD8B1 gene; Cells; Cellular Infiltration; Clinical; Clinical Trials; Data; Disease Progression; Enrollment; Executive Dysfunction; FDA approved; Fumarates; Functional disorder; Glutamates; HIV; HIV Infections; HIV-1; HIV-associated neurocognitive disorder; Hand; Health; 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; Neurocognitive Deficit; Neuropathogenesis; Neuroprotective Agents; Neurotoxins; Outcome; Oxidative Stress; Pathogenesis; Pathway interactions; Patients; Performance; Peripheral Blood Mononuclear Cell; Pharmaceutical Preparations; Pilot Projects; Plasma; Prefrontal Cortex; Prevention; Primates; Proteins; Regimen; SIV; Specimen; Therapeutic; Tissues; Ubiquitination; Validation; Viral Load result; Virus Diseases; antioxidant enzyme; 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; response; success; therapeutic target; trafficking; treatment effect

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：尽管抗逆转录病毒治疗 (ART) 方案的改进显着提高了患者的生存率，但 HIV 相关的神经认知障碍 (HAND) 仍然普遍存在 (~50%)。 在 HAND 中，尽管接受了 ART，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机制，这强调了确定宿主靶点以用于预防 HAND 辅助治疗的迫切需要。我们最近确定了细胞解毒/抗氧化酶血红素加氧酶-1 (HO-1) 作为这样的靶标，并且我们已经证明 HAND 患者的脑组织中 HO-1 表达存在显着缺陷。 我们还确定了最近 FDA 批准的中枢神经系统穿透性多发性硬化症药物（富马酸二甲酯/DMF/Tecfidera(R)），它可以刺激 HO-1 表达，作为预防 HAND 的独特候选神经保护剂。 我们建议定义大脑 HIV-1 感染、HO-1 表达和 HAND 之间的关联，并建立与 HO-1 诱导的概念验证治疗联系，作为 SIV 感染猕猴的富马酸二甲酯/DMF 治疗试验研究中 HAND 神经保护的辅助方法。 使用我们的体外 HIV 神经变性模型，我们表明 HO-1 作为 HIV 诱导的神经变性的特异性抑制剂，并且富马酸二甲酯/DMF 诱导的 HO-1 具有高度的神经保护作用。 通过对 150 多名 HIV+ 个体的尸检脑组织标本（背外侧额叶皮层）进行分析，我们发现 HO-1 表达存在显着缺陷，并表明该 HO-1 缺乏与神经认知（执行）功能障碍相关。 因此，HO-1 大脑缺陷与 HIV 感染者的神经认知功能障碍直接相关，并且一种可能纠正这种缺陷并改善神经认知结果的治疗方法即将到来。 我们假设 HIV 介导的大脑 HO-1 表达抑制有助于 HAND 的神经发病机制，并且在接受 ART 治疗的 HIV+ 个体中用富马酸二甲酯/DMF 诱导 HO-1 表达可以限制与 HAND 相关的神经炎症、神经变性和神经认知衰退。 我们将确定：1）HIV+个体中区域大脑HO-1表达、免疫激活、病毒载量和神经认知表现之间的相关性~2）HIV导致HO-1失调的机制~以及3）DMF治疗是否改变猕猴脑部SIV感染的HO-1表达、神经免疫激活和神经发病机制。