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

基本信息

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
项目类别：
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

项目摘要

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.

项目概要尽管有效，但预防艾滋病毒相关的神经认知障碍（HIV-NCI）仍然难以捉摸 cART 抑制中枢神经系统内的病毒复制，尽管 cART 在 HIV 感染后立即启动。（INSIGHT START 研究）极大地减少了疾病进展，但没有神经认知优势过度延迟的 cART 导致急性脑损伤发生在感染（HIV、SIV）后数周内，然后才进行 cART 抑制。此后通常可能会发生自发的有限恢复，这表明有一个治疗窗口。我们的总体目标是确定快速作用的神经保护治疗。快速同化神经保护药物（富马酸二甲酯/DMF，FDA 批准）的能力，与cART联合使用，可减少恒河猴急性SIV感染的损伤并促进其恢复。 SIV/HIV 损伤与氧化应激和炎症有关，DMF 可以通过增强 Nrf2- 来靶向氧化应激和炎症在我们的人类中驱动抗氧化酶的表达和相关的抗氧化/抗炎途径。脑部尸检研究表明，HIV-NCI 与血红素加氧酶-1 (HO-1) 表达减少相关，抗氧化酶具有两种亚型（HO-1 和 -2），并且会增加神经炎症。没有 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。在另一组 HIV 感染者 (PWH) 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 Nrf2 抗氧化剂。感染巨噬细胞中的酶，并减少 TNFα 和谷氨酸的释放，从而将增强的酶联系起来在恒河猴的急性 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确定了急性突触损伤的独特模式。与低抗氧化酶水平有关，而脑干损伤则与较高的表达有关。神经炎症、酶水平降低以及 HO-2 逐渐丧失，与稳定的 HO-2 相关。在我们的猕猴治疗试验研究中，DMF 诱导大脑抗氧化酶，包括 HO-1，减少 DNA 和蛋白质的氧化，并产生氧化程度较低的大脑氧化还原状态。研究结果支持测试 DMF 作为早期 cART 的辅助手段，我们同时捕获了 DMF 治疗。急性 SIV 感染中的 cART 将减少氧化应激和急性神经元损伤，同时增强神经元我们将确定同时进行的 DMF/cART 对以下方面的影响：（目标 1）区域大脑，氧化损伤、炎症、神经完整性、信号传导和恢复以及与血浆标志物的关联损伤、氧化应激和微生物易位；（目标 2）免疫细胞浸润、细胞的脑定位；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）浸润恒河猴急性 SIV 感染时，大脑和淋巴组织中 SIV 感染的免疫细胞。