Heme Oxygenase-1 as a novel therapeutic target in HIV-mediated neurodegeneration

描述（由申请人提供）：HIV感染导致认知、运动和行为缺陷，统称为HIV相关神经认知障碍（HAND）。尽管有抗逆转录病毒治疗，约50%的HIV患者仍会出现神经认知障碍，这表明需要持续治疗。临床研究表明，HAND中的神经认知障碍与CNS巨噬细胞/小胶质细胞活化相关。活化和HIV感染的单核细胞源性巨噬细胞（HIV-MDM）和小胶质细胞通过可溶性因子介导HAND神经病理学，包括兴奋性神经毒素如谷氨酸，其诱导神经元损伤。HAND患者的CSF中谷氨酸水平升高，这与神经认知障碍和脑萎缩的程度相关。HIV-MDM中调节神经毒素释放（特别是谷氨酸）的内源性途径的鉴定可能为HAND神经变性提供重要的治疗靶点。体内氧化应激标志物与HIV+患者的神经认知功能障碍相关。我们已经明确证明，血红素加氧酶-1（HO-1），哨兵细胞保护性抗氧化反应蛋白，是HIV-MDM神经毒性的关键调节因子。HO-1在HIV-MDM中受到显著抑制，并与谷氨酸产生和神经毒素释放相关。相比之下，HIV-MDM中HO-1诱导减少神经毒素释放，表明HO-1是HAND的新治疗靶点。我们发现HO-1的表达减少，在前额叶皮质的HIV+患者。脑中的HO-1抑制与执行域神经认知障碍、CNS病毒载量和巨噬细胞活化相关。我们将评估HO-1在一组扩大的大脑区域中的区域表达，以确定与相关神经认知领域和HIV疾病进展标志物的相关性。我们还将通过分析HO-1 mRNA和蛋白的表达和稳定性来研究目前未知的HIV-MDM中HO-1抑制机制。最后，我们将扩展我们以前的工作，以进一步确定HO-1诱导减少HIV-MDM神经毒素产生的治疗潜力。特别是，我们将研究富马酸酯（FAE），包括富马酸二甲酯（DMF），作为潜在的治疗候选药物。DMF通过ARE诱导HO-1，穿过血脑屏障，并在多发性硬化症III期临床试验中显示可减少神经炎症。DMF在MS试验中的安全性和有效性、其抗炎特性及其对HO-1的诱导作用强调了其在HAND中的治疗潜力。我们假设HIV+患者CNS中HIV驱动的HO-1抑制驱动巨噬细胞介导的神经变性，通过FAE（如DMF）逆转HO-1缺乏将改善这种神经变性。

DESCRIPTION (provided by applicant): HIV infection causes cognitive, motor, and behavioral deficits collectively known as HIV-associated neurocognitive disorders (HAND). Despite antiretroviral therapy, ~50% of HIV patients continue to develop neurocognitive impairment, affirming a need for adjunctive therapy. Clinical studies have shown that neurocognitive impairment in HAND correlates with CNS macrophage/microglia activation. Activated and HIV-infected monocyte-derived macrophages (HIV-MDM) and microglia mediate HAND neuropathology through soluble factors, including excitatory neurotoxins like glutamate, which induce neuronal injury. HAND patients have increased levels of glutamate in their CSF, which correlates with the degree of neurocognitive impairment and brain atrophy. Identification of endogenous pathways that regulate neurotoxin release, particularly glutamate, in HIV-MDM may provide important therapeutic targets for neurodegeneration in HAND. In vivo markers of oxidative stress correlate with neurocognitive impairment in HIV+ patients. We have specifically demonstrated that heme oxygenase-1 (HO-1), the sentinel cytoprotective antioxidant response protein, is a key regulator of HIV-MDM neurotoxicity. HO-1 is strikingly suppressed in HIV-MDM and correlates to glutamate production and neurotoxin release. In contrast, HO-1 induction in HIV-MDM decreases neurotoxin release, suggesting HO-1 as a novel therapeutic target in HAND. We found HO-1 expression to be decreased in the prefrontal cortex of HIV+ patients. This HO-1 suppression in the brain correlates with executive domain neurocognitive impairment, CNS viral load, and macrophage activation. We will evaluate the regional expression of HO-1 in an expanded panel of brain regions to determine correlations to relevant neurocognitive domains and markers of HIV disease progression. We will also investigate the currently unknown mechanism of HO-1 suppression in HIV-MDM through analysis of HO-1 mRNA and protein expression and stability. Lastly, we will expand upon our previous work to further define the therapeutic potential for HO-1 induction in reducing HIV-MDM neurotoxin production. Particularly, we will study the fumaric acid esters (FAEs), including dimethyl fumarate (DMF), as potential therapeutic candidates. DMF induces HO-1 through the ARE, cross the blood brain barrier, and has been shown to decrease neuroinflammation in multiple sclerosis phase III clinical trials. The safety and efficacy of DMF in MS trials, their anti-inflammatory properties, their induction of HO-1 underscore their therapeutic potential in HAND. We hypothesize that HIV-driven suppression of HO-1 in the CNS of HIV+ patients drives macrophage-mediated neurodegeneration and that reversal of this HO-1 deficiency through FAEs such as DMF will ameliorate this neurodegeneration.