Substance Use and Immunity in HIV+ Adolescents by Systems Biology

项目总结/摘要 在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治疗。 生物标志物监测物质使用对免疫功能和艾滋病毒发病机制的影响， 神经系统尽管随着有效治疗的出现，HIV-1相关性痴呆的发病率有所下降， 由于联合抗逆转录病毒疗法，现在出现了更普遍的认知和运动问题。 神经认知障碍与受感染的青少年特别相关，他们面临终身疾病。影响 药物使用，特别是大麻，对感染艾滋病毒的青少年的神经认知功能， 未知大麻素9-四氢大麻酚[TCH]是大麻中的主要精神活性成分， 靶向脑和中枢神经系统细胞表达的内源性大麻素受体[CB 1]， 以及免疫细胞[CB2]。HIV-1感染和大麻使用对免疫系统的多效性后果 中枢神经系统和外周免疫系统中的炎症反应， 系统，站在HIV-1发病机制和药物滥用之间的界面。系统的组合 人类外周血的生物学和研究为开发全球概况提供了前所未有的机会 复杂的系统，是公正的先入为主的范式和定义多个参数的人类 健康和疾病。拟定研究旨在解决RFA-10 - 014系统的四个关键点 生物学，艾滋病毒/艾滋病，药物滥用，并涉及系统生物学的方法，通过一个互动的多- 调查员纪律小组：1.定义TCH对转录组和蛋白质组的总体影响， 在存在或不存在HIV-1感染的情况下离体培养原代人巨噬细胞。大环藻属 体内为表达CD4的巨噬细胞靶向HIV-1感染提供了模型，以及HIV-1感染的关键调节因子。 炎症、先天免疫和适应性免疫。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联系，以及与HIV-1感染的体内研究的联系， 目标2中提出的人类。2.定义大麻使用和调制之间的关系 一组HIV感染者外周血单个核细胞的整体免疫特征 有或没有神经认知障碍的青少年。通过青少年方案登记的青少年 Trials Network在一项为期三年的抗逆转录病毒治疗对神经认知功能影响的持续研究中 将根据自我报告和血液毒理学评估药物使用情况。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 随着时间总的目标是利用系统生物学来发现与大麻使用有关的新的生物特征 HIV-1感染青少年对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.