Systems Analysis of Inflammatory Pathways in HIV Infection

描述（由申请人提供）：该项目的总体目标是了解在接受抗逆转录病毒治疗（ART）的hiv感染者中控制炎症和抗病毒免疫反应的免疫调节网络和途径。尽管有抗逆转录病毒治疗，慢性炎症仍然是艾滋病毒感染的一个标志，预示着疾病进展和其他不良后果。在初步研究中，我们确定了单核细胞转录组特征，预测hiv感染者在治疗中断期间的保护性抗病毒反应与非保护性炎症反应。然后，我们使用生物信息学软件来预测与炎症细胞因子产生和临床结果差异相关的免疫网络和炎症途径。我们假设，由于肠道渗漏受损而循环的微生物产物，结合特异性促炎细胞因子，PD1/PDL-1和其他未知的宿主因子，通过单核细胞驱动的途径促进抗逆转录病毒治疗的hiv感染者的炎症和功能失调的免疫反应，控制炎症和抗病毒反应之间的平衡。可卡因通过调节IDO/色氨酸代谢途径和先天免疫反应来改变这些途径，促进病理性炎症、功能失调的先天免疫反应和HIV复制。为了研究这一假设，我们将使用系统生物学方法来分析具有不同临床结果的hiv感染者的大规模临床、生物学和组学数据集。综合分析、网络扰动和有针对性的实验将用于计算构建控制炎症与抗病毒反应的网络和途径的模型。这些研究将为控制炎症和免疫反应的机制提供见解，这可能有助于开发新的治疗策略，以改善艾滋病毒感染人群的临床结果。

DESCRIPTION (provided by applicant): The overall goal of this project is to understand immune regulatory networks and pathways that control inflammation and antiviral immune responses in HIV-infected individuals on antiretroviral therapy (ART). Despite ART, chronic inflammation continues to be a hallmark of HIV infection that predicts disease progression and other adverse outcomes. In preliminary studies, we identified monocyte transcriptome signatures that predict protective antiviral responses versus nonprotective inflammatory responses during treatment interruption in HIV-infected individuals. We then used bioinformatic software to predict immune networks and inflammatory pathways linked to differences in inflammatory cytokine production and clinical outcomes. We hypothesize that circulating microbial products due to a leaky damaged gut, in combination with specific proinflammatory cytokines, PD1/PDL-1, and other as yet unknown host factors, promote inflammation and dysfunctional immune responses in HIV-infected individuals on ART through monocyte-driven pathways that control the balance between inflammatory versus antiviral responses. Cocaine alters these pathways by modulating the IDO/tryptophan metabolism pathway and innate immune responses, promoting pathological inflammation, dysfunctional innate immune responses, and HIV replication. To investigate this hypothesis, we will use systems biology approaches to analyze large-scale clinical, biological, and 'omics datasets from HIV-infected subjects with different clinical outcomes. Integrative analysis, network perturbations, and targeted experimentation will be used to computationally build models of networks and pathways that control inflammatory versus antiviral responses. These studies will provide insights into mechanisms that control inflammation and immune responses, which may be helpful for development of new therapeutic strategies to improve clinical outcomes in HIV-infected populations. PUBLIC HEALTH RELEVANCE: This project will use large-scale clinical and biological datasets, computational modeling, and systems biology approaches to identify key regulatory networks and pathways that control the balance between protective antiviral immune responses versus nonprotective inflammatory responses in HIV-infected individuals on antiretroviral therapy. These studies will provide insights into mechanisms that control inflammation and immune responses, which may be helpful for development of new therapeutic strategies to improve clinical outcomes in HIV-infected populations. The studies will also provide a better understanding of mechanisms by which substance abuse, in particular crack cocaine, might adversely affect inflammatory pathways and immune responses in HIV-infected populations.