Poor Sleep and Inflammation in HIV-Infected Adults

Study Overview
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Brief Summary
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People living with HIV (PLWH) often have poor sleep, which may put them at a higher risk for many chronic diseases, including cardiovascular disease. One of the mechanisms by which this may occur is via chronic inflammation and endothelial dysfunction. Adenosine plays an important role in sleep homeostasis, with levels increasing in the CSF in response to sleep deprivation and falling with sleep. Peripherally, adenosine, via its signaling pathway, plays an important role in immunoregulation by suppressing the inflammatory response. PLWH, even on antiretroviral therapy, have suppressed peripheral adenosine levels which are predictive of adverse cardiovascular outcomes. The hypothesis underlying this study is that acute sleep deprivation in PLWH does not result in a compensatory increase in extracellular adenosine and its signaling peripherally, and this failure to appropriately compensate, leads to an increase in systemic inflammation and endothelial dysfunction.

Detailed Description
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People living with HIV infection (PLWH) are known to be at higher risk of cardiovascular disease and also have a higher prevalence of poor sleep than people who do not have HIV infection. Understanding the underlying mechanisms for the elevated risk of cardiovascular disease in PLWH is important to developing novel strategies to mitigate this risk. Poor sleep has been postulated to mediate some of the elevated cardiovascular risk in PLWH given the high prevalence of poor sleep in PLWH and the epidemiologic association of poor sleep with adverse cardiovascular outcomes among people who do not have HIV infection. However, the mechanisms by which PLWH may be more sensitive to sleep loss from a cardiovascular standpoint are unclear. One potential explanation for any elevated sensitivity would be via alterations in the adenosine signaling pathway. Changes in extracellular adenosine levels in the brain and central nervous system play an important homeostatic role in sleep-wake regulation. Sleep deprivation results in a rise in extracellular adenosine levels while sleep itself leads to a rapid decline in levels. Peripheral adenosine signaling is a central feature of immunoregulation, primarily through its effects on inflammatory cytokine expression and lymphocyte adenosine receptor expression. PLWH tend to have a suppressed level of peripheral adenosine signaling and this level of suppression predicts risk of cardiovascular disease. The purpose of this study is to explore the impact of acute sleep deprivation among PLWH on measures of inflammation and endothelial function and to assess the extent to which any changes may be explained by alterations in peripheral adenosine signaling. The study will enroll 40 PLWH, age 18-75, who have been on ART for greater than 48 weeks. Screening with questionnaires, actigraphy and polysomnography will eliminate individuals with underlying chronic sleep abnormalities. A prior night of polysomnography in the sleep lab will also habituate subjects to sleeping while monitored in the sleep lab. Participants will arrive in the sleep laboratory in the evening and be allowed to sleep for 8 hours timed to their usual sleep patterns. On waking, participants will provide a urine sample that will be assayed for adenosine and adenosine metabolites. Blood will be drawn to measure markers of inflammation as well as markers of activation of the peripheral adenosine signaling system. Endothelial function will be assessed using flow mediated dilation. Participants will be kept awake for the subsequent 24 hours including the 8 hour normal sleep period. On the second morning, subjects will again provide urine and blood samples for the same bioassays described above and then undergo repeat assessment of endothelial function.

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

Conditions
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HIV-1-infection, Sleep Deprivation, Inflammation

Intervention / Treatment
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* Behavioral: Sleep deprivation


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: HIV positive On continuous anti-retroviral therapy regimen for at least 48 weeks CD4+ cell count greater than or equal to 200 cells/mm^3 Exclusion Criteria: Irregular or insufficient habitual sleep patterns Severe advanced or delayed sleep phase Primary sleep disorder Autoimmune disorder Use of immunosuppressant medications Use of medications impacting adenosine pathway Heavy caffeine use Active alcohol or drug abuse Elevated risk of adverse health effects from sleep deprivation (e.g., bipolar disorder, epilepsy, or suicidal ideation in the past 6 months) Pregnancy

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 75 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Basic Science
Intervention Model: Single Group Assignment
Interventional Model Description: All participants will undergo one night of normal sleep (Night 1) followed by a subsequent night (Night 2) of sleep deprivation. Outcomes will be assessed the morning (Day 1 and Day 2) after each condition.
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Sleep deprivation<br>All subjects will be provided an 8 hour opportunity for sleep (Night 1) followed by outcome assessment the next morning (Day 1). They will then be kept awake the subsequent 24 hours including Night 2, followed by outcome assessment the following morning (Day 2). | Behavioral: Sleep deprivation<br>* Eight hour opportunity for sleep followed by 24 hours of sleep deprivation.<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Soluble CD14 | Plasma concentration of soluble CD14 | Baseline sleep replete state and after 24 hours of sleep deprivation | 
| Soluble CD163 | Plasma concentration of soluble CD163 | Baseline sleep replete state and after 24 hours of sleep deprivation | 
| IL6 | Plasma concentration of interleukin-6 | Baseline sleep replete state and after 24 hours of sleep deprivation | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Flow Mediated Brachial Artery Dilation | Percent change was calculated by measuring the brachial artery diameter at baseline and then the percent dilation from this baseline after release of occlusion at each time point. | Baseline sleep replete state and after 24 hours of sleep deprivation | 
| Monocyte Expression of IL6 | Percentage of circulating CD14+ peripheral blood mononuclear cells expressing interleukin-6 | Baseline sleep replete state and after 24 hours of sleep deprivation | 
| Monocyte Expression of TNF-alpha | Percentage of circulating CD14+ peripheral blood mononuclear cells expressing tumor necrosis factor-alpha | Baseline sleep replete state and after 24 hours of sleep deprivation | 
| CD4+ T-cell Expression of HLA-DR and CD38 | Percentage of CD3+ CD4+ T-lymphocytes co-expressing HLA-DR and CD38 | Baseline sleep replete state and after 24 hours of sleep deprivation | 
| CD8+ T-cell Expression of HLA-DR and CD38 | Percentage of CD3+ CD8+ T-lymphocytes co-expressing HLA-DR and CD38 | Baseline sleep replete state and after 24 hours of sleep deprivation | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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adenosine