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

摘要

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.