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

描述：尽管由于抗逆转录病毒治疗（ART）方案的改进，患者生存率显著提高，但HIV相关神经认知障碍（HAND）仍然普遍存在（~50%）。在HAND中，尽管抗逆转录病毒治疗，中枢神经系统炎症和氧化应激仍然存在，并继续促进神经发病机制，这强调了确定辅助治疗HAND预防的宿主靶点的迫切需要。我们最近发现细胞解毒/抗氧化酶血红素加氧酶-1 （HO-1）是这样一个靶标，我们已经证明HO-1在HAND患者的脑组织中表达明显不足。我们还确定了最近fda批准的穿透中枢神经系统的多发性硬化症药物（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。我们建议确定脑HIV-1感染、HO-1表达和HAND之间的关系，并在一项针对siv感染小鼠的富马酸二甲酯/ dmf治疗中试研究中，建立HO-1诱导作为HAND神经保护辅助方法的概念验证治疗联系。通过体外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因子，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+个体的脑组织解剖标本（背外侧额叶皮层）的分析，我们发现HO-1的表达明显不足，并表明这种HO-1具有明显的特异性

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.