COCAINE USE AND HIV ANTIRETROVIRAL THERAPY EFFICACY IN THE CNS

可卡因的使用和 HIV 抗逆转录病毒治疗在中枢神经系统中的疗效

• 批准号: 10226215
• 负责人: Dionna Whitney Williams
• 金额: $ 24.26万
• 依托单位: JOHNS HOPKINS UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2019
• 资助国家: 美国
• 起止时间: 2019-09-30 至 2022-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10226215
• 关键词: ABCB1 gene; Address; Affect; Anti-Retroviral Agents; Area; Autopsy; Award; Blood - brain barrier anatomy; Brain; Bypass; CYP3A4 gene; Characteristics; Cocaine; Cocaine Users; Cognitive deficits; Consequences of HIV; Cytochrome P450; Dementia; Development; Disease Progression; Dose; Drug Efflux; Drug Transport; Effectiveness; Ensure; Environment; Enzymes; Exhibits; Family; Foundations; Genetic; Genetic Polymorphism; Goals; HIV; HIV Infections; HIV antiretroviral; HIV-1; HIV-associated neurocognitive disorder; Human; Image; Impaired cognition; Incidence; Individual; Innate Immune Response; International; Life Expectancy; Local Therapy; Macaca; Mass Spectrum Analysis; Mediating; Mentorship; Metabolic Pathway; Metabolism; Methodology; Microglia; Minor; Modality; Modeling; Molecular Biology; Multidrug Resistance-Associated Proteins; Neuraxis; Neurologic; Neurons; Neuropathogenesis; OATP Transporters; Pathogenesis; Pathway interactions; Peripheral; Pharmaceutical Preparations; Pharmacogenetics; Pharmacology; Phase; Plasma; Prevalence; Primary Infection; Quality of life; RNA Interference; Research; Research Personnel; Resources; Risk; SIV; Series; Severities; Spatial Distribution; Spectrometry, Mass, Matrix-Assisted Laser Desorption-Ionization; Substance abuse problem; Therapeutic; Training; Treatment Efficacy; Universities; Viral Load result; Viral reservoir; Viremia; Virus; Virus Replication; Work; antiretroviral therapy; blood-brain barrier permeabilization; brain parenchyma; career development; cellular targeting; cocaine use; cognitive function; comorbidity; drug abuser; experience; macrophage; mass spectrometric imaging; meetings; neuroinflammation; non-drug; pandemic disease; programs; research and development; response; seropositive; skills; substance abuser; therapeutic target

Project Summary/Abstract Human immunodeficiency virus-1 (HIV) enters the central nervous system (CNS) early after primary infection and results in a spectrum of cognitive deficits, collectively termed HIV associated neurocognitive disorders (HAND). While successful in reducing peripheral viral loads to undetectable levels, antiretroviral therapy (ART) does not effectively quell CNS viremia to the same extent. As a result, ART has not decreased the prevalence of HAND, which continues to increase as the life expectancy for seropositive individuals rises. HIV-infected substance abusers exhibit more severe cognitive impairment compared with their non-drug abusing counterparts. Specifically, cocaine use is associated with an accelerated incidence and progression of HAND. This occurs, in part, due to cocaine-mediated increases in HIV replication and resultant blood-brain barrier perturbations, neuroinflammatory responses, and neuronal damage that contribute to the sequelae characteristic of HAND. To understand more fully the impact of cocaine use on the pathogenesis of HAND, I will examine three major mechanisms by which cocaine may interfere with ART effectiveness in the CNS. In Aim 1, I will evaluate the impact of cocaine on ART metabolism by HIV infected macrophages/microglia. These analyses will occur during the K99 phase. Aim 2 will also be performed during the K99 phase, where I will determine the distribution of ART in the brain during comorbid HIV infection and cocaine use by mass spectrometric imaging. In the R00 phase of the award, I will characterize the association between polymorphisms in drug metabolizing enzymes and HAND during Aim 3. Finally, Aim 4 will be performed in the remainder of the R00 phase where I will evaluate the transport of ART across the BBB in the context of cocaine. My past experience with the blood-brain barrier, HAND, and substance abuse will be combined with my current training in CNS-specific innate immune responses and the molecular biology of HIV pathogenesis. However, I require additional training in pharmacology of ART, mass spectrometric modalities, and pharmacogenetics. The institutional resources and outstanding mentorship available at the Johns Hopkins University provide a supportive and rich training environment in which to develop an independent research program. In the K99 phase, I will receive mentorship from a team of distinguished leaders in their respective fields: Drs. Clements, Bumpus, McArthur, and Haughey. Under their guidance and with their support, I will receive technical training in experimental concepts and development of appropriate methodologies, which will be complimented by networking opportunities at national and international scientific meetings. Successful completion of the mentorship, didactic training, research, and career development activities afforded by this K99/R00 Pathway to Independence Award will provide the strong foundation necessary for my successful transition to an independent investigator.

项目概要/摘要 人类免疫缺陷病毒 1 (HIV) 在初次感染后早期进入中枢神经系统 (CNS) 并导致一系列认知缺陷，统称为艾滋病毒相关神经认知障碍 （手）。抗逆转录病毒治疗 (ART) 成功地将外周病毒载量降低至不可检测的水平 不能在相同程度上有效地平息中枢神经系统病毒血症。因此，ART 并没有降低患病率 HAND 的数量随着血清阳性个体预期寿命的延长而持续增加。艾滋病毒感染者 与非药物滥用者相比，药物滥用者表现出更严重的认知障碍 同行。具体而言，可卡因的使用与 HAND 的发病率和进展加速有关。 发生这种情况的部分原因是可卡因介导的艾滋病毒复制增加以及由此产生的血脑屏障 导致后遗症的扰动、神经炎症反应和神经元损伤 手的特征。为了更全面地了解可卡因使用对 HAND 发病机制的影响，我 将研究可卡因可能干扰中枢神经系统 ART 有效性的三种主要机制。在 目标 1，我将评估可卡因对 HIV 感染的巨噬细胞/小胶质细胞 ART 代谢的影响。这些 分析将在 K99 阶段进行。目标2也将在K99阶段进行，我将在其中 确定 HIV 共病感染和可卡因使用期间 ART 在大脑中的分布 光谱成像。在奖项的 R00 阶段，我将描述以下之间的关联： 目标 3 期间药物代谢酶和 HAND 的多态性。最后，目标 4 将在 在 R00 阶段的剩余部分，我将在以下背景下评估 ART 跨 BBB 的运输： 可卡因。我过去在血脑屏障、HAND 和药物滥用方面的经验将与 我目前接受的培训是中枢神经系统特异性先天免疫反应和艾滋病毒发病机制的分子生物学。 然而，我需要额外的 ART 药理学、质谱模式和 药物遗传学。约翰·霍普金斯大学提供的机构资源和出色的指导 大学为开展独立研究提供支持性和丰富的培训环境 程序。在K99阶段，我将接受来自各自领域杰出领导者团队的指导 领域： 博士。克莱门茨、邦普斯、麦克阿瑟和豪伊。在他们的指导和支持下，我会 接受实验概念和适当方法开发方面的技术培训，这将 获得国家和国际科学会议上的交流机会。成功的 完成本项目提供的指导、教学培训、研究和职业发展活动 K99/R00 独立之路奖将为我的成功提供必要的坚实基础 过渡为独立调查员。