Understanding the association of sleep on monocyte action in HIV infection

PROJECT SUMMARY/ABSTRACT
As a sleep-medicine physician, I seek to understand how sleep health affects the progression and long-term
consequences of chronic disease and, ultimately, implement sleep-based interventions to improve the health of
patients. Sleep disorders are highly prevalent among people with HIV (PWH), and emerging evidence suggests
that sleep disorders may increase the risk of cardiovascular disease in PWH. Sleep disorders, such as
obstructive sleep apnea (OSA) and insufficient sleep duration, are recognized as indepdent risk factors for
cardiovascular risk. However, little is known about how sleep disorders worsen chronic inflammation among
PWH. One understudied pathway by sleep disorders may increase inflammation and cardiovascular risk is by
promoting monocyte activation. PWH experience chronic monocyte dysregulation despite antiretroviral therapy,
and those with a greater burden of monocyte activation are at an higher risk of developing cardiovascular
disease. Monocytes from individuals exposed to OSA or insufficient sleep exhibit markers of monocyte activation,
such as greater production of proinflammatory cytokines and expression of cellular adhesion markers. Various
stimuli have been found to contribute to excessive monocyte activation, but the impact of sleep disorders on
monocyte activation in PWH has not been investigated. I hypothesize that PWH are vulnerable to amplified
monocyte activation from exposure to the “second hit” of a sleep disorder. In Aims 1 and 2, I will utilize stored
samples to evaluate monocyte activation in PWH by chronic and acute sleep exposure, respectively. Aims 1a
and 1b will investigate if OSA and insufficient sleep are a) associated with a monocyte activation phenotype in
PWH and b) explore if there is a differential effect of sleep disorder exposure on monocyte activation profiles by
HIV status. In Aim 2, I will quantify the impact of acute sleep deprivation on monocyte activation among PWH
who participated in an acute sleep deprivation protocol. In Aim 3, I will prospectively enroll PWH with OSA and
evaluate the impact of OSA treatment on reducing monocyte activation among PWH. Lastly, in Aims 4a and 4b,
I will utilize stored and prospectively enrolled samples utilized in Aims 2 and 3 to investigate differences in gene
expression in circulating monocytes a) before and after acute sleep deprivation and b) before and after treatment
of OSA, respectively. If successful, this proposal will identify a biological mechanism by which sleep disorders
contribute to HIV-associated inflammation, identifying a targetable pathey to reduce CVD risk in PWH by either
sleep-based or pharmacologic interventions. Through completing the proposed experiments alongside formal
didactic education and intensive mentorship, I will develop my expertise in HIV-associated inflammation and
immunophenotyping, develop new skills in systems immunology, and gain experience in conducting human
subjects sleep research. This proposal takes advantage of the robust resources and research environment at
the University of Pittsburgh, which includes my excellent mentorship team to support my development as an
independent-physician scientist.

Grant Number: 3K23HL169022-03S1
NIH Institute/Center: NIH
Principal Investigator: Priya Borker