Systems Analysis of Inflammatory Pathways in HIV Infection

项目摘要/摘要 这个项目的总体目标是了解免疫调节网络和控制 抗逆转录病毒治疗(ART)中HIV感染者的炎症和抗病毒免疫反应。 尽管抗逆转录病毒治疗，慢性炎症仍然是艾滋病毒感染的标志，预示着疾病的发生。 进展和其他不良后果。在初步研究中，我们发现了单核细胞转录组 预测保护性抗病毒反应与非保护性炎症反应的特征 艾滋病毒感染者的治疗中断。然后，我们使用生物信息学软件来预测免疫 与炎性细胞因子产生和临床差异有关的网络和炎症途径 结果。我们假设，由于肠道泄漏受损，循环中的微生物产物与 特定的促炎细胞因子PD1/PDL-1和其他未知的宿主因子促进炎症 单核细胞驱动的抗逆转录病毒治疗后HIV感染者的免疫功能障碍反应 控制炎症反应和抗病毒反应之间的平衡。可卡因通过以下方式改变这些途径 调节IDO/色氨酸代谢途径和先天免疫反应，促进病理 炎症、功能失调的先天免疫反应和艾滋病毒复制。为了研究这一假设，我们 将使用系统生物学方法来分析来自艾滋病毒的大规模临床、生物和组学数据集- 不同临床结局的感染者。综合分析、网络扰动和有针对性的 实验将被用来通过计算建立控制网络和路径的模型 炎症反应与抗病毒反应。这些研究将提供对控制 炎症和免疫反应，这可能有助于开发新的治疗策略 改善艾滋病毒感染人群的临床结果。

Project Summary/Abstract 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.