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.

项目总结/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HIV相关神经认知障碍 （手）。虽然成功地将外周病毒载量降低到无法检测的水平，但抗逆转录病毒治疗（ART） 不能有效地抑制CNS病毒血症到相同的程度。因此，抗逆转录病毒疗法并没有降低 随着血清反应阳性者预期寿命的延长，HAND的发病率继续上升。hiv感染 药物滥用者比非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。 这部分是由于可卡因介导的HIV复制增加和由此产生的血脑屏障 扰动、神经炎症反应和神经元损伤导致后遗症 手的特点。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CNS中ART有效性的三种主要机制。在 目的1，我将评估可卡因对HIV感染的巨噬细胞/小胶质细胞的ART代谢的影响。这些 分析将在K99阶段进行。目标2也将在K99阶段执行，我将 确定艾滋病毒感染和可卡因使用共病期间ART在大脑中的分布 光谱成像在该奖项的R 00阶段，我将描述 Aim 3期间药物代谢酶和HAND的多态性。最后，目标4将在 R 00阶段的剩余部分，我将在以下背景下评价ART通过BBB的转运： 可卡因我过去对血脑屏障、手和药物滥用的经验将与 我目前在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方面的培训。 然而，我需要额外的培训，在药理学的艺术，质谱模式， 药物遗传学约翰霍普金斯大学的机构资源和优秀的导师 大学提供了一个支持和丰富的培训环境，在其中发展独立的研究 程序.在K99阶段，我将接受一个由杰出领导者组成的团队的指导， 克莱门茨博士，邦普斯，麦克阿瑟和豪伊。在他们的指导和支持下，我将 接受实验概念和制定适当方法方面的技术培训， 通过在国家和国际科学会议上建立联系的机会来加以补充。成功 完成导师，教学培训，研究，和职业发展活动提供了这一点 K99/R 00独立之路奖将为我的成功奠定坚实的基础 过渡到独立调查员。