Substance Use and Immunity in HIV+ Adolescents by Systems Biology

描述(申请人提供)：HIV-1感染患者的临床管理中的一个重要问题是缺乏基于血液的生物标记物来监测物质使用对中枢神经系统免疫功能和艾滋病毒发病的影响。尽管随着有效的联合抗逆转录病毒疗法的出现，HIV-1相关性痴呆症的发病率有所下降，但认知和运动问题的患病率现在有所上升。神经认知障碍与感染的青少年尤其相关，他们面临终身疾病。药物使用，特别是大麻对感染艾滋病毒的青少年神经认知功能的影响尚不清楚。大麻素-9-四氢大麻酚[TCH]是大麻中的主要精神活性成分，其靶标是脑细胞和中枢神经系统[CB1]以及免疫细胞[CB2]表达的内源性大麻素受体。HIV-1感染和大麻使用对免疫失调的多重影响，以及中枢神经系统和外周免疫系统的炎症反应，处于HIV-1发病机制和药物滥用之间的交界处。系统生物学和人类外周血研究的结合为开发复杂系统的全球概况提供了前所未有的机会，这些复杂系统不受先入为主的范例的偏见，并定义了人类健康和疾病的多个参数。拟议的研究旨在解决RFA-10-014系统生物学、艾滋病毒/艾滋病和药物滥用的四个关键点，并由一个互动的多学科研究团队涉及系统生物学方法，以：1.确定在存在或不存在HIV-1感染的情况下，TCH对体外原代人类巨噬细胞转录和蛋白质组的整体影响。巨噬细胞体外为HIV-1感染的CD4表达巨噬细胞靶标以及炎症、先天免疫和获得性免疫的关键调节因子提供了模型。该方法对于理解HIV-1感染和人类药物使用之间的接口以及与目标2中提出的关于人类HIV-1感染的体内研究之间的联系是基本的。2.在有或没有神经认知障碍的HIV感染青少年队列中，确定大麻使用和外周血单个核细胞全球免疫图谱调节之间的关系。通过青少年试验网络登记的青少年参加了一项为期三年的正在进行的关于抗逆转录病毒治疗对神经认知功能的影响的研究，将根据自我报告和血液毒理学评估药物使用情况。随着时间的推移，外周血细胞转录组的系统生物学研究将与血浆和细胞表面蛋白质组学相结合。总体目标是使用系统生物学来发现新的生物特征，这些生物特征将大麻的使用和免疫与HIV-1感染青少年的神经认知障碍联系起来。 公共卫生相关性：拟议的研究使用系统生物学策略开发新的生物图谱，将大麻使用与原代人类巨噬细胞的免疫功能障碍联系起来，并在体内系统地与HIV-1感染青少年的神经认知障碍联系起来。系统生物学和对人类外周血的研究相结合，为发现复杂系统的全球概况提供了前所未有的机会，这些系统不受先入为主的范例的偏见。结果将转化为改善青少年HIV-1相关神经认知障碍的诊断、预后和治疗。

DESCRIPTION (provided by applicant): A significant problem in the clinical management of HIV-1 infected patients is a lack of blood based biomarkers to monitor the effects of substance use on immune function and HIV pathogenesis in the central nervous system. Although incidence of HIV-1 associated dementia has declined with the advent of effective combination antiretroviral therapies, a greater prevalence of cognitive and motor problems now develop. Neurocognitive impairment is particularly relevant to infected adolescents, who face life-long disease. Impact of substance use, in particular marijuana, on neurocognitive functioning among HIV-infected adolescents is unknown. The cannabinoid delta-9-tetrahydrocannabinol [TCH], the main psychoactive component in marijuana, targets endogenous cannabinoid receptors expressed by cells of brain and central nervous system [CB1], as well as by immune cells [CB2]. Pleiotropic consequences of HIV-1 infection and marijuana use on immune dysregulation, and the inflammatory response in the central nervous system and in the peripheral immune system, stand at the interface between HIV-1 pathogenesis and substance abuse. Combination of systems biology and studies of human peripheral blood provide an unprecedented opportunity to develop global profiles of complex systems that are unbiased by preconceived paradigms and define multiple parameters of human health and disease. Proposed studies are designed to address the four key points of RFA-10-014 Systems Biology, HIV/AIDS, and Substance Abuse and involve systems biology approaches by an interactive multi-disciplinary team of investigators to: 1. Define the global effects of TCH on transcriptome and proteome of primary human macrophages ex vivo in the presence or absence of HIV-1 infection. Macrophages ex vivo provide models for CD4-expressing macrophage targets for HIV-1 infection, as well as key regulators of inflammation, innate and adaptive immunity. The approach is fundamental to understanding the interface between HIV-1 infection and substance use in humans and links with in vivo studies of HIV-1 infection in humans proposed in Objective 2. 2. Define the relationship between marijuana use and modulation of global immune profiles in peripheral blood mononuclear cells within a cohort of HIV-infected adolescents with or without neurocognitive impairment. Adolescents enrolled through the Adolescent Trials Network in a three-year ongoing study of the effects of antiretroviral therapy on neurocognitive function will be assessed for substance use, based on self-reporting and blood toxicology. A systems biology study of peripheral blood cell transcriptome at end of study will be combined with plasma and cell-surface proteomics over time. The overall goal is to use systems biology to discover novel bioprofiles that relate use of marijuana and immunity to neurocognitive impairment in HIV-1 infected adolescents. PUBLIC HEALTH RELEVANCE: The proposed studies use systems biology strategy to develop novel bioprofiles that relate marijuana use to immune dysfunction in primary human macrophages ex vivo and systemically in vivo with neurocognitive impairment in HIV-1 infected adolescents. Combination of systems biology and studies of human peripheral blood provide an unprecedented opportunity to discover global profiles of complex systems that are unbiased by preconceived paradigms. Outcomes will translate to improved diagnosis, prognosis and treatment of HIV-1 associated neurocognitive impairment in adolescents.