Protection against early SIV brain injury with adjunctive therapy to cART

项目摘要 预防艾滋病毒相关的神经认知障碍（HIV-NCI）仍然难以捉摸，尽管有效的 cART抑制CNS内的病毒复制。尽管cART在HIV感染后立即启动， （INSIGHT START研究）显著降低了疾病进展，没有神经认知优势 延迟的cART急性脑损伤发生在感染（HIV，SIV）的几周内，在cART抑制之前， 通常实现。此后可能会发生自发性有限恢复，这表明治疗窗口 速效神经保护疗法这些还没有经过测试。我们的总体目标是确定 一种快速吸收的神经保护药物（富马酸二甲酯/DMF，FDA批准）， 与cART组合，以减少恒河猴中急性SIV感染的损伤并促进恢复。 SIV/HIV损伤与氧化应激和炎症有关，DMF可以通过增强Nrf 2- 驱动的抗氧化酶表达和相关的抗氧化/抗炎途径。我们人类 脑尸检研究，HIV-NCI与血红素氧合酶-1（HO-1）表达减少相关， 抗氧化酶有两种亚型（HO-1和HO-2），神经炎症增加。此外，艾滋病毒 没有HIV-NCI的感染与HO-1水平增加相关，这与HO的神经保护作用一致。 在另一组HIV感染者中，我们发现HO-1启动子变异（（GT）n 二核苷酸重复）），增强HO-1表达，与较低的神经炎症和较低的HIV-1相关。 NCI风险。在急性HIV感染（体外）中，我们发现DMF诱导HO-1和其他Nrf 2抗氧化剂 酶，并减少TNF α和谷氨酸盐的释放，从而将增强的酶 表达与神经保护。在恒河猴的急性SIV感染中，我们确定了一种潜在的治疗方法， DMF增强抗氧化反应的窗口。我们发现了急性突触损伤的独特模式 与低抗氧化酶水平和表达变化有关。脑干损伤与高血压相关 神经炎症，酶水平降低和HO-2的进行性丢失。与稳定HO-2相关的恢复 增加HO-1水平。在我们的猕猴初步治疗研究中，DMF诱导脑抗氧化酶， 包括HO-1，减少DNA和蛋白质的氧化，并产生较少氧化的脑氧化还原状态。这些 研究结果支持将DMF作为早期cART的辅助治疗。我们假设DMF治疗与 急性SIV感染中的cART将减少氧化应激和急性神经元损伤，同时增强神经元损伤。 整个大脑的恢复。我们将确定同时DMF/cART对以下方面的影响：（目标1）局部脑， 氧化损伤、炎症、神经元完整性、信号传导和恢复，以及与血浆标志物的相关性 损伤、氧化应激和微生物易位的影响;（目的2）免疫细胞浸润、细胞 免疫、内皮、神经胶质和神经元亚型中的活化和氧化损伤;以及（目的3） 恒河猴急性SIV感染时脑和淋巴组织中SIV感染的免疫细胞。

Project Summary Prevention of HIV-associated neurocognitive impairment (HIV-NCI) remains elusive, despite the efficacy of cART in suppressing viral replication within the CNS. Although cART initiated immediately after HIV infection (INSIGHT START study) profoundly reduced disease progression, there was no neurocognitive advantage over delayed cART. Acute brain injury occurs within weeks of infection (HIV, SIV), before cART suppression is typically achieved. Spontaneous limited recovery may occur thereafter, suggesting a therapeutic window for rapid-acting neuroprotective treatments. These have not yet been tested. Our overall objective is to determine the ability of a rapidly-assimilated neuroprotective drug (dimethyl fumarate/DMF, FDA-approved), in combination with cART, to reduce injury and promote recovery in acute SIV infection in rhesus macaques. SIV/HIV injury is linked to oxidative stress and inflammation, which DMF can target through enhancing Nrf2- driven antioxidant enzyme expression and associated antioxidative/anti-inflammatory pathways. In our human brain autopsy studies, HIV-NCI associated with reduced expression of heme oxygenase-1 (HO-1), an antioxidant enzyme with two isoforms (HO-1 and -2), and with increased neuroinflammation. Moreover, HIV infection without HIV-NCI associated with increased HO-1 levels, consistent with a neuroprotective role for HO. In a separate cohort of persons living with HIV (PWH), we showed that an HO-1 promoter variation ((GT)n dinucleotide repeat)) that enhances HO-1 expression, associates with lower neuroinflammation and lower HIV- NCI risk. In acute HIV infection (in vitro) we showed that DMF induces HO-1 and other Nrf2 antioxidant enzymes in infected macrophages, and reduces TNF and glutamate release, thus linking enhanced enzyme expression with neuroprotection. In acute SIV infection in rhesus macaques, we defined a potential therapeutic window for DMF enhancement of antioxidant responses. We identified unique patterns of acute synaptic injury linked to low antioxidant enzyme levels, and changes in expression. Brainstem injury associated with higher neuroinflammation, lower enzyme levels, and progressive loss of HO-2. Recovery associated with stable HO-2 and increasing HO-1 levels. In our pilot macaque treatment study, DMF induced brain antioxidant enzymes, including HO-1, reduced oxidation of DNA and proteins, and produced a less-oxidized brain redox state. These findings support testing DMF as an adjunct to early cART. We hypothesize that DMF therapy concurrently with cART in acute SIV infection will reduce oxidative stress and acute neuronal injury while enhancing neuronal recovery throughout the brain. We will determine effects of concurrent DMF/cART on: (Aim 1) regional brain, oxidative injury, inflammation, neuronal integrity, signaling and recovery, and association with plasma markers of injury, oxidative stress and microbial translocation; (Aim 2) brain localization of immune cell infiltration, cell activation and oxidative injury in immune, endothelial, glial, and neuronal subtypes; and (Aim 3) infiltration of SIV-infected immune cells in brain and lymphatic tissue, in acute SIV infection of rhesus macaques.