COCAINE USE AND HIV ANTIRETROVIRAL THERAPY EFFICACY IN THE CNS

项目摘要/摘要 人类免疫缺陷病毒1型(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性神经认知障碍 (手)。虽然成功地将外周病毒载量降低到无法检测的水平，但抗逆转录病毒疗法(ART) 不能有效地平息同样程度的中枢神经系统病毒血症。因此，抗逆转录病毒治疗并没有降低患病率。 随着血清阳性个体预期寿命的增加，这一比例继续增加。艾滋病病毒感染者 与非吸毒者相比，吸毒者表现出更严重的认知障碍 对口单位。具体地说，可卡因的使用与手部疾病的发生和发展加速相关。 这在一定程度上是由于可卡因导致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、神经炎性反应和神经元损伤 以手为特征的。为了更全面地了解可卡因使用对手部疾病发病机制的影响，我 将研究可卡因可能通过三种主要机制干扰中枢神经系统的ART效果。在……里面 目的1、评价可卡因对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阶段执行，在那里我将 人群感染HIV和吸食可卡因期间ART在脑内的分布 光谱成像。在颁奖的R00阶段，我将描述两者之间的关联 目标3期间药物代谢酶和手部的多态。最后，目标4将在 R00阶段的剩余部分，我将在以下背景下评估BBB中的艺术品运输 可卡因。我过去在血脑屏障、手和药物滥用方面的经验将与 我目前接受的培训是针对中枢神经系统的先天免疫反应和艾滋病毒发病机制的分子生物学。 然而，我需要在ART的药理学，质谱学模式，和 药物遗传学。约翰·霍普金斯大学的机构资源和杰出的导师 大学提供支持和丰富的培训环境，在其中开展独立研究 程序。在K99阶段，我将接受来自他们各自的杰出领导者团队的指导 菲尔兹：克莱门茨博士、本普斯博士、麦克阿瑟博士和豪伊博士。在他们的指导和支持下，我将 接受实验概念和开发适当方法方面的技术培训，这将 在国家和国际科学会议上建立联系的机会是值得称赞的。成功 完成指导、授课培训、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 过渡到一个独立的调查员。

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.