Impact of illicit drugs, HIV, and ART on neuroinflammation and BBB disruption

非法药物、艾滋病毒和抗逆转录病毒治疗对神经炎症和血脑屏障破坏的影响

• 批准号: 10153747
• 负责人: Joan Weinberger Berman
• 金额: $ 75.23万
• 依托单位: ALBERT EINSTEIN COLLEGE OF MEDICINE
• 依托单位国家: 美国
• 财政年份: 2017
• 资助国家: 美国
• 起止时间: 2017-07-01 至 2024-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10153747
• 关键词: ALCAM gene; Astrocytes; Binding; Blood; Blood - brain barrier anatomy; Brain; Brain Injuries; CCL2 gene; CD14 gene; Cell Adhesion Molecules; Cell Death; Cells; Central Nervous System Diseases; Central Nervous System Infections; Chronic; Cognitive deficits; Data; Development; Disease; Dopamine; Drug Modelings; Drug abuse; Endothelial Cells; FCGR3B gene; Goals; HIV; HIV Induced T Cell Apoptosis Pathway; HIV Infections; HIV Seropositivity; HIV therapy; Human; Illicit Drugs; Impaired cognition; In Vitro; Individual; Infection; Inflammation; Inflammation Mediators; Inflammatory; Integrin alpha4beta1; Intervention; METH abuser; Macrophage Activation; Mediating; Mediator of activation protein; Methamphetamine; Microglia; Modeling; Molecular; Neurons; Neuropathogenesis; Peripheral; Pharmacotherapy; Play; Process; Production; Proteins; Quality of life; Regimen; Role; SIV; Substance abuse problem; Substance of Abuse; Techniques; Tenofovir; Testing; Therapeutic; Transgenic Mice; Viral; Viral Load result; Viral Proteins; antiretroviral therapy; base; blood-brain barrier disruption; blood-brain barrier permeabilization; brain cell; chemokine; cognitive function; cytokine; drug of abuse; extracellular; immune activation; improved; in vivo; innovation; intercellular cell adhesion molecule; macrophage; methamphetamine effect; methamphetamine use; migration; monocyte; mouse model; neuroinflammation; novel; peripheral blood; prevent; protein expression; therapeutic target; therapy development

We propose is to examine molecular mechanisms of HIV-mediated inflammation in the presence of antiretroviral therapy (ART) and drugs of abuse. Substance abuse often exacerbates neuroinlammation. We will use methamphetamine (meth) as it has been shown to enhance HIV CNS disease, and dopamine as a model for drug abuse as all substances of abuse increase CNS extracellular dopamine. HIV infection of the CNS results in chronic inflammation that leads to cognitive deficits in more than 50% of infected people. This inflammation and subsequent CNS damage is not mitigated with ART. Thus, triggering inflammation is a key process in HIV disease and therapies to limit immune activation and neuroinflammation must be developed to improve the quality of life of HIV infected people. HIV enters the CNS soon after peripheral infection and despite ART, persists within infected cells. HIV entry into the brain is mediated, at least in part, by infected monocyte transmigration across the blood brain barrier (BBB). A mature subset of monocytes that expresses CD14 and CD16 is a key mediator of HIV CNS disease and is increased in number in the peripheral blood of HIV infected people. These monocytes are productively infected with HIV and are primed to cross the BBB. Within the CNS, HIV infected monocytes may differentiate into macrophages that can persist for years. This leads to infection/activation of CNS cells, resulting in chronic neuroinflammation with the production of virus and/or viral proteins, cytokines and chemokines. Chemokines, in particular CCL2, increase transmigration of peripheral blood monocytes, continuing neuroinflammation. Thus, chronic inflammation is thought to mediate neuronal damage in a large percentage of infected individuals by mechanisms not well understood. We will characterize the effects of meth, HIV and tat, and ART on monocyte entry into the CNS and on subsequent neuroinflammation. We will test potential therapeutics to limit inflammation and guide efficacy of ART. We hypothesize that meth use combines with HIV infection to exacerbate neuroinflammation and compromise BBB integrity, increasing transmigration of uninfected and HIV-infected monocytes into the brain, leading to cognitive impairment. Based on our new preliminary data that tenofovir increases junctional proteins on the BBB, we also hypothesize that certain ART regimens, especially in meth abusers, may negatively impact cognitive function by synergizing with meth to increase BBB permeability and neuroinflammation. We will characterize effects of meth, HIV and tat, and ART on cytokines, chemokines, and adhesion molecules elaborated by and expressed on CD14+CD16+ monocytes that facilitate entry into the CNS, and in causing BBB permeability and transmigration of CD14+CD16+ monocytes resulting in inflammation, and the impact of ART. We will use a murine model to evaluate the in vivo impact of meth, HIV and its proteins, and ART on BBB permeability and migration of inflammatory cells into the brain. We will also examine effects of meth or dopamine, HIV tat, and ART on cytokine release from CNS cells that mediate inflammation.

我们的目的是研究HIV介导的炎症的分子机制， 抗逆转录病毒疗法和滥用药物。药物滥用常使神经炎症恶化。我们 将使用甲基苯丙胺（冰毒），因为它已被证明可以增强HIV CNS疾病，多巴胺作为一种 药物滥用模型，因为所有滥用物质都会增加CNS细胞外多巴胺。艾滋病病毒感染者 CNS导致慢性炎症，导致超过50%的感染者认知缺陷。这 ART不能减轻炎症和随后的CNS损伤。因此， 必须开发限制免疫激活和神经炎症的治疗方法， 提高艾滋病毒感染者的生活质量。HIV在外周感染后很快进入CNS， 尽管有抗逆转录病毒疗法，它仍然存在于受感染的细胞内。HIV进入大脑至少部分是由感染的 单核细胞穿越血脑屏障（BBB）。单核细胞的成熟亚群，表达 CD 14和CD 16是HIV CNS疾病的关键介质， 艾滋病毒感染者。这些单核细胞被HIV有效地感染，并准备穿过BBB。 在CNS内，HIV感染的单核细胞可分化成巨噬细胞，其可持续数年。这 导致CNS细胞感染/活化，导致慢性神经炎症和病毒产生 和/或病毒蛋白、细胞因子和趋化因子。趋化因子，特别是CCL 2，增加了 外周血单核细胞，持续神经炎症。因此，慢性炎症被认为是介导 在很大比例的感染个体中，神经元损伤的机制尚不清楚。我们将 表征甲氨蝶呤、HIV和达特以及ART对单核细胞进入CNS以及随后的 神经炎症我们将测试潜在的治疗方法，以限制炎症并指导ART的疗效。 假设冰毒使用与HIV感染相结合会加剧神经炎症并损害BBB 完整性，增加未感染和HIV感染的单核细胞进入大脑的迁移，导致 认知障碍根据我们新的初步数据，替诺福韦增加了细胞表面的连接蛋白， BBB，我们还假设某些ART方案，特别是在冰毒滥用者中， 通过与甲氨蝶呤协同增加BBB渗透性和神经炎症来增强认知功能。我们将 表征甲氨蝶呤、HIV和达特以及ART对细胞因子、趋化因子和粘附分子的影响 由CD 14 + CD 16+单核细胞精心制作并在其上表达，促进进入CNS，并引起 BBB通透性和CD 14 + CD 16+单核细胞的迁移导致炎症，以及 条我们将使用小鼠模型来评估冰毒、艾滋病毒及其蛋白以及ART对BBB的体内影响 炎性细胞向脑中的渗透性和迁移。我们还将研究冰毒的影响， 多巴胺、HIV达特和ART对介导炎症的CNS细胞释放细胞因子的影响。