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.