Protection against early SIV brain injury with adjunctive therapy to cART

cART 辅助治疗可预防早期 SIV 脑损伤

• 批准号: 10402475
• 负责人: Dennis Larry Kolson
• 金额: $ 85.48万
• 依托单位: UNIVERSITY OF PENNSYLVANIA
• 依托单位国家: 美国
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-03-15 至 2027-02-28
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10402475
• 关键词: AIDS prevention; Acute; Acute Brain Injuries; Address; Anti-Inflammatory Agents; Antioxidants; Astrocytes; Autopsy; Biological Markers; Brain; Brain Injuries; Brain Stem; Cells; Cellular Infiltration; Chemotaxis; Corpus striatum structure; DNA; Dinucleotide Repeats; Disease Progression; Drug usage; Endothelium; Enzymes; FDA approved; Fumarates; Future; Genetic Variation; Glutamates; Goals; HIV; HIV Infections; Heme; Hour; Human; Image; Immune; Immunologic Deficiency Syndromes; Immunologic Markers; Infection; Infiltration; Inflammation; Inflammatory Response; Injury; Lead; Link; Lymphoid Tissue; Macaca; Macaca mulatta; Macrophage Activation; Meninges; Microglia; Modeling; Neurocognitive; Neurocognitive Deficit; Neuronal Injury; Neurons; Neuroprotective Agents; Optics; Oxidation-Reduction; Oxidative Stress; Oxides; Oxygenases; Pathway interactions; Patients; Pattern; Persons; Pharmaceutical Preparations; Pilot Projects; Plasma; Protein Isoforms; Proteins; Recovery; Risk; Role; SIV; Signal Transduction; Structure of choroid plexus; Synapses; T-Lymphocyte; TNF gene; Terminal Disease; Testing; Therapeutic; Tissues; Variant; Viral load measurement; Virus; Virus Replication; antioxidant enzyme; antiretroviral therapy; brain tissue; cohort; heme oxygenase-1; heme oxygenase-2; immune activation; in vivo; injury recovery; macrophage; microbial; monocyte; multiple sclerosis treatment; neuroinflammation; neuroprotection; oxidation; oxidative damage; prevent; promoter; response; response biomarker; response to injury; treatment strategy

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.

项目摘要 预防与HIV相关的神经认知障碍（HIV-NCI）仍然难以捉摸 推车抑制中枢神经系统内的病毒复制。虽然在艾滋病毒感染后立即启动卡车 （洞察开始研究）大大降低了疾病的进展，没有神经认知优势 延迟的购物车。急性脑损伤发生在感染后数周之内（HIV，SIV），在抑制卡车之前 通常实现。此后可能发生自发的有限恢复，这暗示了一个治疗窗口 快速作用神经保护治疗。这些尚未经过测试。我们的总体目标是确定 快速综合的神经保护药（富马酸二甲基/DMF，FDA批准）的能力，在 与购物车结合使用，以减少恒河猕猴中急性SIV感染的损伤并康复。 SIV/HIV损伤与氧化应激和注射有关，DMF可以通过增强NRF2-靶向。 驱动的抗氧化剂酶表达和相关的抗氧化/抗炎途径。在我们的人类中 脑尸检研究，HIV-NCI与血红素氧酶-1（HO-1）的表达降低有关 具有两种同工型（HO -1和-2）的抗氧化剂酶，并具有增加的神经炎症。而且，艾滋病毒 没有HIV-NCI的感染与HO-1水平升高有关，与HO的神经保护作用一致。 在单独的艾滋病毒（PWH）的人群中，我们表明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相关联 NCI风险。在急性HIV感染（在体外）中，我们表明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TNF和谷氨酸释放，从而连接增强的酶 神经保护表达。在恒河猕猴中的急性SIV感染中，我们定义了潜在的治疗 DMF增强抗氧化剂反应的窗口。我们确定了急性突触损伤的独特模式 与低抗氧化剂酶水平以及表达变化有关。脑干损伤与更高有关 神经炎症，较低的酶水平和HO-2的进行性丧失。与稳定HO-2相关的恢复 并增加HO-1水平。在我们的试验猕猴治疗研究中，DMF诱导脑抗氧化剂酶， 包括HO-1，减少DNA和蛋白质的氧化，并产生氧化较少的脑氧化还原态。这些 调查结果支持测试DMF作为早期购物车的辅助手段。我们假设DMF治疗同时 急性SIV感染中的手推车将减少氧化应激和急性神经元损伤，同时增强神经元 整个大脑恢复。我们将确定并发DMF/CART的影响：（ AIM 1）区域大脑， 氧化损伤，感染，神经元完整性，信号传导和恢复，以及与等离子体标记的关联 损伤，氧化应激和微生物易位； （目标2）免疫细胞浸润，细胞的大脑定位 免疫学，内皮，神经胶质和神经元亚型的激活和氧化损伤； （目标3） SIV感染的脑和淋巴组织中SIV的免疫细胞，猕猴的急性SIV感染。