Protection against early SIV brain injury with adjunctive therapy to cART

项目摘要 预防艾滋病毒相关性神经认知障碍(HIV-NCI)仍然难以捉摸，尽管 CART在抑制中枢神经系统内的病毒复制方面的作用。尽管CART在HIV感染后立即启动 (Insight Start研究)深刻降低疾病进展，没有神经认知优势 由于手推车延误。急性脑损伤发生在感染(HIV，SIV)的几周内，在CART抑制之前 通常是实现的。之后可能会出现自发的有限恢复，这表明有一个治疗窗口 快速有效的神经保护治疗。这些都还没有经过测试。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)在 与CART联合应用，减轻猕猴SIV急性感染的损伤，促进其康复。 SIV/HIV损伤与氧化应激和炎症有关，DMF可以通过增强Nrf2- 驱动抗氧化酶的表达和相关的抗氧化/抗炎途径。在我们人类身上 脑尸检研究，HIV-NCI与血红素氧合酶-1(HO-1)表达减少相关，以及 具有两种异构体(HO-1和-2)的抗氧化物酶，以及增加的神经炎症。此外，艾滋病毒 无HIV-NCI的感染与HO-1水平升高相关，这与HO的神经保护作用一致。 在单独的艾滋病毒携带者(PWH)队列中，我们发现HO-1启动子变异((GT)n 二核苷酸重复))，增强HO-1的表达，与较低的神经炎症和较低的艾滋病毒- NCI风险。在急性HIV感染(体外)中，我们发现DMF诱导HO-1和其他Nrf2抗氧化剂 感染巨噬细胞中的酶，并减少肿瘤坏死因子和谷氨酸的释放，从而连接增强的酶 具有神经保护作用的表情。在猕猴急性SIV感染中，我们定义了一种潜在的治疗方法 DMF增强抗氧化反应的窗口。我们确定了急性突触损伤的独特模式 与抗氧化酶水平低有关，以及表达的变化。脑干损伤与更高的 神经炎症，酶水平降低，HO-2进行性丧失。与稳定的HO-2相关的恢复 升高HO-1水平。在我们的猕猴治疗试验中，DMF诱导大脑抗氧化物酶， 包括HO-1，减少了DNA和蛋白质的氧化，并产生了较少氧化的大脑氧化还原状态。这些 研究结果支持将DMF作为早期购物车的辅助工具进行测试。我们假设DMF治疗与 急性SIV感染的CART可减轻氧化应激和急性神经元损伤，同时增强神经元 整个大脑的恢复。我们将确定并发DMF/CART对以下方面的影响：(目标1)区域脑， 氧化损伤、炎症、神经元完整性、信号和恢复以及与血浆标记物的相关性 损伤、氧化应激和微生物移位；(目标2)脑内免疫细胞浸润、细胞定位 免疫、内皮、神经胶质和神经元亚型的激活和氧化损伤；以及(目标3)渗透 SIV感染猕猴的脑组织和淋巴组织中的免疫细胞。

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.