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

产品说明：HIV相关的神经认知障碍（HAND）仍然很普遍（约50%），尽管由于抗逆转录病毒治疗（ART）方案的改进，患者的生存率显著提高。 在HAND中，尽管有ART，CNS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HAND预防的连续治疗的宿主靶点的迫切需要。我们最近确定了细胞解毒/抗氧化酶，血红素加氧酶-1（HO-1），作为这样一个目标，我们已经证明了一个显着的不足HO-1的表达在脑组织中的个人与手。 我们还确定了最近FDA批准的CNS穿透性多发性硬化症药物（富马酸二甲酯/DMF/Tecfidera（R）），其刺激HO-1表达，作为预防HAND的独特候选神经保护剂。 我们建议定义脑HIV-1感染、HO-1表达和HAND之间的关联，并在SIV感染猕猴的富马酸二甲酯/DMF治疗试验研究中建立与HO-1诱导的概念验证治疗联系，作为HAND神经保护的连续方法。 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HO-1具有高度神经保护作用。 通过分析来自150多名HIV阳性个体的尸检脑组织标本（背外侧额叶皮层），我们发现HO-1表达明显不足，并表明这种HO-1 缺乏与神经认知（执行）功能障碍相关。 因此，HO-1大脑缺陷与艾滋病毒感染者的神经认知功能障碍直接相关，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介导的脑HO-1表达抑制有助于HAND的神经发病机制，并且在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下降。 我们将确定：1）HIV+个体中局部脑HO-1表达、免疫激活、病毒载量和神经认知性能之间的相关性~ 2）HIV引起的HO-1失调机制~和3）DMF处理是否改变猕猴脑SIV感染的HO-1表达、神经免疫激活和神经发病机制。

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.