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治疗，但HIV感染与认知和 神经行为障碍，统称为neuroHIV。艾滋病毒和阿片类药物独立地与 血脑屏障（BBB）功能障碍、炎症信号传导的改变以及认知和运动缺陷。 HIV病毒蛋白质达特被认为介导了大脑中大部分与HIV相关的损伤。这 该提案将使用达特转基因小鼠模型和鼠嗜性HIV感染小鼠模型。达特 转基因小鼠模型表达由GFAP启动子驱动的HIV-1达特，这限制了CNS的表达。 这两种模型将用于检查体内HIV和吗啡的作用。我们的核心假设是， 阿片类药物损害BBB功能，并通过复杂的机制导致神经病理学， 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， 增加单核细胞的浸润和增加脑内的炎症信号。我们将解决我们的 有以下具体目标的假设。目标1。确定阿片类药物± HIV-1达特和HIV感染的影响 对BBB完整性和功能以及对抗逆转录病毒药物和吗啡浓度的区域特异性影响 在大脑中。目标二。描述阿片类药物± HIV/HIV-1达特和 抗逆转录病毒药物对巨噬细胞向中枢神经系统浸润和中枢神经系统促炎细胞因子产生的影响。这些 研究将确定阿片类药物和/或HIV-1对区域药物蓄积，BBB完整性， 药物代谢/外排，以及免疫细胞运输到脑内和脑内的炎症信号。更好 对这种动态相互作用的理解，特别是对抗逆转录病毒药物脑浓度的理解， 目前对使用阿片类药物（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如何限制ARV在脑内的治疗效果， 并确定治疗发展的目标，以消除阿片剂/艾滋病毒对 神经认知结果。