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

描述：HIV相关神经认知障碍(HAND)仍然很普遍(~50%)，尽管由于改进的抗逆转录病毒治疗(ART)方案显著改善了患者的存活率。另一方面，尽管抗逆转录病毒治疗，中枢神经系统的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点用于辅助治疗以预防手部疾病的迫切需要。我们最近确定了细胞解毒/抗氧化酶，血红素加氧酶-1(HO-1)，作为这样的靶点，我们已经证明，在手部疾病患者的脑组织中，HO-1的表达明显不足。我们还确定了FDA最近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的表达，是预防手部疾病的唯一候选神经保护剂。我们建议确定脑HIV-1感染、HO-1表达和手部之间的联系，并在SIV感染小鼠的先导性富马酸二甲酯/DMF治疗研究中，建立与HO-1诱导的概念验证治疗联系，作为手部神经保护的辅助方法。使用我们的体外HIV神经变性模型，我们发现HO-1是HIV诱导的神经变性的特异性抑制者，并且富马酸二甲酯/DMF诱导HO-1具有高度的神经保护作用。通过对150多名HIV阳性患者的尸检标本(额叶背外侧皮质)的分析，我们发现了HO-1表达的显著缺陷，并表明这一HO-1 缺乏与神经认知(执行)功能障碍相关。因此，HO-1脑缺陷与艾滋病毒感染者的神经认知功能障碍直接相关，一种有可能纠正这一缺陷并改善神经认知结果的治疗方法即将问世。我们假设HIV介导的脑HO-1表达抑制参与了手部的神经发病，在接受ART治疗的HIV+患者中，富马酸二甲酯/DMF诱导HO-1的表达可以限制与手部相关的神经炎症、神经变性和神经认知能力下降。我们将确定：1)HIV+个体局部脑HO-1表达、免疫激活、病毒载量和神经认知功能之间的相关性；2)HIV~+对HO-1调节失调的机制；3)DMF治疗是否改变了HO-1的表达、神经免疫激活和猕猴脑SIV感染的神经发病机制。

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.