Substance Use and Immunity in HIV+ Adolescents by Systems Biology

描述（由申请人提供）：在HIV-1感染患者的临床管理中，一个重要的问题是缺乏基于血液的生物标志物来监测药物使用对免疫功能和中枢神经系统HIV发病机制的影响。尽管HIV-1相关痴呆的发病率随着有效的抗逆转录病毒联合疗法的出现而下降，但现在认知和运动问题的发病率更高。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。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的影响尚不清楚。大麻素δ -9-四氢大麻酚（cannabinoid delta-9-tetrahydrocannabinol， TCH）是大麻的主要精神活性成分，作用于脑和中枢神经系统细胞[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效性影响，以及中枢神经系统和外周免疫系统的炎症反应，是HIV-1发病机制和药物滥用之间的界面。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，这些系统不受先入为主的范例的影响，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，并通过一个互动的多学科研究小组涉及系统生物学方法：1。确定TCH在存在或不存在HIV-1感染的情况下对体外原代人巨噬细胞转录组和蛋白质组的整体影响。体外巨噬细胞为HIV-1感染的cd4表达巨噬细胞靶点以及炎症、先天免疫和适应性免疫的关键调节因子提供了模型。该方法对于理解人类HIV-1感染与物质使用之间的界面以及与目标2中提出的人类HIV-1感染的体内研究的联系至关重要。2. 确定大麻使用与有或无神经认知障碍的hiv感染青少年外周血单个核细胞整体免疫谱调节之间的关系。青少年试验网络正在进行一项为期三年的研究，研究抗逆转录病毒治疗对神经认知功能的影响，将根据自我报告和血液毒理学评估青少年的药物使用情况。研究结束时，外周血细胞转录组的系统生物学研究将随着时间的推移与血浆和细胞表面蛋白质组学相结合。总体目标是利用系统生物学发现新的生物特征，将大麻的使用与HIV-1感染青少年的神经认知障碍免疫联系起来。

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.