SASH: Poor Sleep and Inflammation in HIV-Infected Adults
Study Details
Study Description
Brief Summary
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.
| Condition or Disease | Intervention/Treatment | Phase |
|---|---|---|
|
N/A |
Detailed Description
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.
Study Design
Arms and Interventions
| Arm | Intervention/Treatment |
|---|---|
| Experimental: Sleep deprivation 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
Eight hour opportunity for sleep followed by 24 hours of sleep deprivation.
|
Outcome Measures
Primary Outcome Measures
- Change in soluble CD14 [Baseline and immediately after sleep deprivation]
Change in plasma concentration of soluble CD14 from baseline
- Change in soluble CD163 [Baseline and immediately after sleep deprivation]
Change in plasma concentration of soluble CD163 from baseline
- Change in IL6 [Baseline and immediately after sleep deprivation]
Change in plasma concentration of interleukin-6 from baseline
Secondary Outcome Measures
- Change in flow mediated brachial artery dilation [Baseline and immediately after sleep deprivation]
Change in percent change in maximal brachial artery diameter after arterial occlusion
- Change in monocyte expression of IL6 [Baseline and immediately after sleep deprivation]
Change in percentage of circulating CD14+ peripheral blood mononuclear cells expressing IL-6
- Change in monocyte expression of TNF-alpha [Baseline and immediately after sleep deprivation]
Change in percentage of circulating CD14+ peripheral blood mononuclear cells expressing TNF-alpha
- Change in CD4+ T-cell expression of HLA-DR and CD38 [Baseline and immediately after sleep deprivation]
Change in percentage of CD3+ CD4+ T-lymphocytes co-expressing HLA-DR and CD38
- Change in CD8+ T-cell expression of HLA-DR and CD38 [Baseline and immediately after sleep deprivation]
Change in percentage of CD3+ CD8+ T-lymphocytes co-expressing HLA-DR and CD38
Other Outcome Measures
- Change in plasma adenosine [Baseline and immediately after sleep deprivation]
Change in plasma adenosine concentration
- Change in plasma inosine [Baseline and immediately after sleep deprivation]
Change in plasma inosine concentration
- Change in urine 3'5'-cAMP [Baseline and immediately after sleep deprivation]
Change in urine 3'5'-cyclic adenosine monophosphate concentration normalized to creatinine
- Change in CD4+ T-cell expression of CD39 and/or CD73 [Baseline and immediately after sleep deprivation]
Change in percentage of CD3+ CD4+ T-lymphocytes expressing CD39 and/or CD73
- Change in CD8+ T-cell expression of CD39 and/or CD73 [Baseline and immediately after sleep deprivation]
Change in percentage of CD3+ CD8+ T-lymphocytes expressing CD39 and/or CD73
Eligibility Criteria
Criteria
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
Contacts and Locations
Locations
| Site | City | State | Country | Postal Code | |
|---|---|---|---|---|---|
| 1 | University of Pittsburgh | Pittsburgh | Pennsylvania | United States | 15260 |
Sponsors and Collaborators
- University of Pittsburgh
- National Heart, Lung, and Blood Institute (NHLBI)
Investigators
- Principal Investigator: Sanjay R Patel, MD, University of Pittsburgh
- Principal Investigator: Bernard J Macatangay, MD, University of Pittsburgh
Study Documents (Full-Text)
None provided.More Information
Publications
None provided.- PRO17120573
- R01HL142118