Opioid- and HIV-mediated effects on the integrity of the blood-brain barrier, on immune cell recruitment, and on antiretroviral penetration into the brain

阿片类药物和艾滋病毒介导的对血脑屏障完整性、免疫细胞募集以及抗逆转录病毒渗透到大脑的影响

• 批准号: 10376839
• 负责人: Mary Peace McRae
• 金额: $ 52.94万
• 依托单位: VIRGINIA COMMONWEALTH UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2021
• 资助国家: 美国
• 起止时间: 2021-04-01 至 2022-12-01
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10376839
• 关键词: ABCB1 gene; ABCG2 gene; Address; Amantadine; Animal Model; Anti-Retroviral Agents; Blood - brain barrier anatomy; Blood Vessels; Brain; Brain region; Carrier Proteins; Cells; Cognitive; Cognitive deficits; Complex; Dantrolene; Data; Drug Exposure; Drug Transport; Event; Feedback; Functional disorder; Glial Fibrillary Acidic Protein; Goals; Grant; HIV; HIV Infections; HIV antiretroviral; HIV-1; Immune; Immunofluorescence Immunologic; Impaired cognition; Impairment; Individual; Infection; Infiltration; Inflammation; Inflammatory; Knowledge; Measures; Mediating; Metformin; Modeling; Morphine; Mus; Nerve Degeneration; Neurocognitive; Neurocognitive Deficit; Neuroimmune; Opioid; Outcome; Pathogenesis; Penetration; Permeability; Pharmaceutical Preparations; Population; Production; Quinidine; RNA Interference; Reporting; Role; Signal Transduction; Therapeutic; Time; Toxic effect; Transgenic Mice; Transgenic Organisms; Treatment Efficacy; Tumor-infiltrating immune cells; Viral Proteins; Work; antiretroviral therapy; arm; base; blood damage; blood-brain barrier function; carvedilol; cytokine; drug metabolism; human model; improved; in vivo; in vivo Model; inhibitor; macrophage; mass spectrometric imaging; monocyte; morphine-3-glucuronide; motor deficit; mouse model; neuroAIDS; neurobehavioral; neuroinflammation; neuropathology; neurotoxic; opioid abuse; opioid exposure; opioid use; patients who use opioids; promoter; protein expression; recruit; regional difference; targeted treatment; tat Protein; therapeutic development; trafficking

Despite aggressive use of combination antiretroviral therapy, HIV infection is associated with cognitive and neurobehavioral impairment, collectively termed neuroHIV. HIV and opiates are independently associated with blood brain barrier (BBB) dysfunction, alterations in inflammatory signaling, and cognitive and motor deficits. The HIV viral protein Tat is thought to mediate much of the HIV-associated damage within the brain. This proposal will use both a Tat transgenic mouse model and a murine tropic HIV-infected mouse model. The Tat transgenic mouse model expresses HIV-1 Tat driven by a GFAP promotor, which limits expression to the CNS. The two models will be used to examine the effects of HIV and morphine in vivo. Our central hypothesis is that opiates compromise BBB function and contribute to neuropathology through complex mechanisms which include enhancing paracellular flux, while paradoxically decreasing net flux of antiretrovirals across the barrier, increasing infiltration of monocytes, and increasing inflammatory signals within the brain. We will address our hypotheses with the following specific aims. Aim 1. Define the effects of opiates ± HIV-1 Tat and HIV infection on BBB integrity and function and on region-specific impact on antiretrovirals and morphine concentrations within the brain. Aim 2. Characterize regional differences in the interplay between opiates ± HIV/HIV-1 Tat and ARVs on macrophage infiltration into the CNS and on proinflammatory cytokine production the CNS. These studies will define and relate the effects of opiates and/or HIV-1 on regional drug accumulation, BBB integrity, drug metabolism/efflux, and immune cell trafficking into and inflammatory signals within the brain. Better understanding of this dynamic interplay, with specific focus on antiretroviral brain concentrations, will improve the current therapeutic approaches for the HIV patients who use opioids (for licit or illicit use). The long-term goal is to understand how opiates limit ARV therapeutic efficacy within the brain in the setting of HIV and to identify targets for therapeutic development to eliminate the negative effects of opiates/HIV on neurocognitive outcomes.

尽管积极使用联合抗逆转录病毒疗法，HIV 感染仍与认知和认知能力相关。 神经行为障碍（统称为神经艾滋病毒）和阿片类药物独立相关。 血脑屏障（BBB）功能障碍、炎症信号改变以及认知和运动缺陷。 HIV 病毒蛋白 Tat 被认为介导了大部分与 HIV 相关的大脑损伤。 该提案将使用 Tat 转基因小鼠模型和鼠类 HIV 感染小鼠模型。 转基因小鼠模型表达由 GFAP 启动子驱动的 HIV-1 Tat，该启动子限制了中枢神经系统的表达。 这两个模型将用于检查艾滋病毒和吗啡在体内的影响。我们的中心假设是： 阿片类药物会损害 BBB 功能，并通过复杂的机制促进神经病理学， 包括增强细胞旁通量，同时矛盾地减少抗逆转录病毒药物穿过屏障的净通量， 单核细胞浸润增加，大脑内炎症信号增加。 具有以下具体目标的假设 目标 1. 定义阿片类药物 ± HIV-1 Tat 和 HIV 感染的影响。 血脑屏障完整性和功能以及抗逆转录病毒药物和吗啡浓度的区域特异性影响 目标 2. 描述阿片类药物 ± HIV/HIV-1 Tat 和 HIV/HIV-1 Tat 之间相互作用的区域差异。 抗逆转录病毒药物对中枢神经系统巨噬细胞浸润和中枢神经系统促炎细胞因子产生的影响。 研究将定义和关联阿片类药物和/或 HIV-1 对区域药物积累、血脑屏障完整性、 药物代谢/流出、免疫细胞流入大脑和炎症信号更好。 对这种动态相互作用的理解，特别关注抗逆转录病毒脑浓度，将提高 当前使用阿片类药物（合法或非法使用）的艾滋病毒患者的治疗方法。 长期目标是了解阿片类药物在以下情况下如何限制大脑内的抗逆转录病毒治疗效果： 艾滋病毒并确定治疗开发目标，以消除阿片类药物/艾滋病毒对人体的负面影响 神经认知结果。