Substance Use and Immunity in HIV+ Adolescents by Systems Biology

项目摘要/摘要 HIV-1感染者临床管理中的一个重要问题是缺乏血液基础。 监测药物使用对免疫功能和HIV致病机制影响的生物标志物 神经系统。尽管随着有效药物的出现，HIV-1相关性痴呆症的发病率有所下降 结合抗逆转录病毒治疗，认知和运动问题的患病率更高。 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。影响 物质使用，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 未知。大麻中的主要精神活性成分--大麻素--9-四氢大麻酚， 靶向脑细胞和中枢神经系统细胞表达的内源性大麻素受体[CB1]，AS 以及免疫细胞[CB2]。HIV-1感染和大麻使用对免疫的多效性影响 中枢神经系统和外周免疫中的炎症反应 系统，站在艾滋病毒-1致病机理和药物滥用之间的界面上。系统组合 生物学和对人类外周血的研究为建立全球概况提供了前所未有的机会 不受先入为主的范式的偏见并定义人类的多个参数的复杂系统 健康和疾病。建议的研究旨在解决RFA-10-014系统的四个关键点 生物学，艾滋病毒/艾滋病和药物滥用，并涉及系统生物学的方法，通过互动的多 纪律调查小组：1.确定TCH对转录组和蛋白质组的全球影响 原代人巨噬细胞在存在或不存在HIV-1感染的情况下的体外实验。巨噬细胞除外 Vivo为HIV-1感染的CD4表达巨噬细胞靶点以及关键调控因子提供了模型 炎症、先天免疫和获得性免疫。该方法是理解接口的基础 人类HIV-1感染与药物使用之间的关系及其与HIV-1体内感染研究的联系 人类在目标2.2中提出。定义大麻使用和调节 HIV感染者队列中外周血单核细胞的全球免疫图谱 有或没有神经认知障碍的青少年。通过青少年招募的青少年 抗逆转录病毒治疗对神经认知功能影响的三年持续研究中的试验网络 将根据自我报告和血液毒理学对药物使用情况进行评估。生物多样性的系统生物学研究 研究结束时的外周血细胞转录组将与血浆和细胞表面蛋白质组学相结合 随着时间的推移。总体目标是使用系统生物学来发现与大麻使用有关的新的生物特征。 以及对感染HIV-1的青少年的神经认知障碍的免疫力。

Project Summary/Abstract 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 ¿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.