Impact of Poor Sleep on Inflammation and the Adenosine Signaling Pathway in HIV Infection

摘要 艾滋病毒感染，尽管开发和实施了抗逆转录病毒疗法(ART)，但与 高水平的炎症，这似乎是导致早产风险升高的主要因素 艾滋病毒携带者中的心血管和肺部疾病。我们小组最近的研究发现 腺苷信号通路受损是导致不能正常工作的重要机制 调节促炎途径。腺苷信号也是正常睡眠觉醒的关键成分 基底前脑和中枢神经系统其他部分细胞外腺苷水平的调节 作为体内平衡睡眠动力的生化驱动力。长期睡眠不佳，这是高度 在艾滋病毒携带者中流行，已被证明改变了中枢神经系统中的腺苷信号 系统和急性睡眠剥夺已被发现改变白细胞中腺苷受体的表达。 流行病学和实验数据表明，急性和慢性睡眠中断都会导致睡眠质量升高 炎症以及人们经历的许多相同的下游心肺健康后果 艾滋病毒携带者。我们发现在HIV()人群中自我报告的睡眠不佳是一个独立的预测因素 心肺疾病。在这项提议中，我们试图测试一种假设，即睡眠不佳的一种机制 可能通过对外周腺苷信号的影响来影响炎症和心肺风险。我们会 评估客观评估的睡眠习惯、炎症和心肺疾病之间的关系 ART治疗的HIV()人群中的标志物，并比较与HIV(-)对照组的关系。在 设定HIV感染后，我们将进一步比较T细胞免疫激活和外周血腺苷水平 在有和没有慢性睡眠剥夺的人中发出信号，以评估慢性睡眠习惯对 艾滋病毒携带者之间的腺苷信号通路。最后，我们将评估24小时的影响 急性睡眠剥夺对腺苷信号、炎症、免疫激活和血管内皮细胞功能的影响 有健康睡眠习惯的HIV()人群评估急性睡眠不足对外周腺苷的影响 信号和下游效应。总之，这些实验将评估睡眠不良对炎症的作用 和心肺功能，并评估急性睡眠丧失的程度 慢性睡眠障碍影响艾滋病毒的炎症和免疫功能以及缺陷在 外周腺苷信号转导这些效应。这项工作将提供关于小说的洞察力 预防HIV长期心血管和肺部并发症的治疗策略 感染。

ABSTRACT HIV infection, despite the development and implementation of antiretroviral therapy (ART), is associated with high levels of inflammation, which appears to be a major factor underlying the elevated risk for premature cardiovascular and pulmonary disease among people living with HIV. Recent work from our group identifies impairments in the adenosine signaling pathway as an important mechanism leading to an inability to normally regulate pro-inflammatory pathways. Adenosine signaling is also a key component to normal sleep-wake regulation, with extracellular adenosine levels in the basal forebrain and other parts of the central nervous system serving as the biochemical driver of the homeostatic drive for sleep. Chronically poor sleep, which is highly prevalent among people living with HIV, has been demonstrated to alter adenosine signaling in the central nervous system and acute sleep deprivation has been found to alter adenosine receptor expression in leukocytes. Epidemiologic and experimental data suggest both acute and chronic disruption of normal sleep leads to elevated inflammation and to many of the same downstream cardiopulmonary health consequences experienced by people living with HIV. We have found self-reported poor sleep in an HIV(+) population is an independent predictor of cardiopulmonary disease. In this proposal, we seek to test the hypothesis that one mechanism by which poor sleep may impact inflammation and cardiopulmonary risk is via effects on peripheral adenosine signaling. We will assess the association between objectively assessed sleep habits, inflammation and cardiopulmonary disease markers in an ART-treated HIV(+) population and compare relationships with an HIV(-) control group. In the setting of HIV infection, we will further compare levels of T-cell immune activation and peripheral adenosine signaling in those with and without chronic sleep deprivation to assess the impact of chronic sleep habits on adenosine signaling pathways among people living with HIV. Finally, we will assess the impact of 24 hours of acute sleep deprivation on adenosine signaling, inflammation, immune activation, and endothelial function in an HIV(+) population with healthy sleep habits to assess the impact of acute sleep loss on peripheral adenosine signaling and downstream effects. In total, these experiments will evaluate the role of poor sleep on inflammation and cardiopulmonary function in people living with HIV and evaluate the extent to which both acute sleep loss and chronic sleep disruption impact inflammation and immune function in HIV and the role of defects in peripheral adenosine signaling in mediating these effects. This work will provide insights regarding novel therapeutic strategies towards preventing the long term cardiovascular and pulmonary complications of HIV infection.