Associations of cytokines, sleep patterns, and neurocognitive function in youth with HIV infection

https://doi.org/10.1016/j.clim.2012.04.004Get rights and content

Abstract

Youth infected with HIV at birth often have sleep disturbances, neurocognitive deficits, and abnormal psychosocial function which are associated with and possibly resulted from elevated blood cytokine levels that may lead to a decreased quality of life. To identify molecular pathways that might be associated with these disorders, we evaluated 38 HIV-infected and 35 uninfected subjects over 18-months for intracellular cytokine levels, sleep patterns and duration of sleep, and neurodevelopmental abilities. HIV infection was significantly associated with alterations of intracellular pro-inflammatory cytokines (TNF-α, IFN-γ, IL-12), sleep factors (total time asleep and daytime sleep patterns), and neurocognitive factors (parent and patient reported problems with socio-emotional, behavioral, and executive functions; working memory–mental fatigue; verbal memory; and sustained concentration and vigilance. By better defining the relationships between HIV infection, sleep disturbances, and poor psychosocial behavior and neurocognition, it may be possible to provide targeted pharmacologic and procedural interventions to improve these debilitating conditions.

Highlights

► HIV infection is associated with changes in cytokines, sleep, and neurocognition. ► TNF-α, IFN-γ, and IL-12 appear to impact sleep duration in youth with HIV. ► Youth with HIV infection seem to require more daytime sleep than controls. ► HIV infection, cytokines and increased sleep may worsen neurocognitive measures. ► Adherence to HIV drugs and better sleep habits may be treatment strategies for youth.

Introduction

HIV infection often produces altered sleep-regulating hormones and cytokine levels [1], [2], [3], sleep problems and fatigue [4], [5], abnormal neurocognitive and psychosocial function, and a increased frequency of psychotic illness and early dementia [5], [6], [7], [8], [9], [10], [11], [12], [13], as well as impaired immune function [14], [15], [16], [17], [18]. In turn, poor sleep and fatigue are related to altered patterns of growth hormone secretion in children with HIV infection [19]. The one report of sleep disturbances in children with HIV infection [20] did not address a molecular mechanism or assess neurocognitive deficits that might result from these sleep disturbances. The effects of impaired sleep and increased fatigue on HIV disease progression, neurocognitive function, and psychosocial behavior in HIV-infected children can potentially impair school performance, future employment, and general quality of life. It is also unclear whether altered production of sleep-regulating hormones and cytokines is associated with the sleep abnormalities and the neuropsychological deficits seen in these children.

More than 2.5 million children and adolescents worldwide have perinatally-acquired HIV infection, and 40% of the yearly-incident 50,000 HIV infections in the U.S. occur in adolescents and young adults [21], so there is an urgency to understand the possible effects of HIV infection on immune responses, sleep patterns, and neurocognitive and psychosocial function. Such an understanding will require a multidisciplinary investigation into the clinical and physiological aspects of these symptoms, their causes and possible treatment. Entry of the estimated 20,000 newly HIV-infected U.S. youth each year into higher education and the work force has been addressed by providing flexible academic and workplace schedules, peer support groups, and balancing patients' medical care times with educational and workplace responsibilities [22]. We report here the results of a cohort study in which HIV-infected children and uninfected children were compared for differences in cytokine production, sleep patterns, and neurocognitive function.

Section snippets

Patients and recruitment strategies

This study was approved by the Institutional Review Boards of Baylor College of Medicine (BCM) and Texas Children's Hospital (TCH), Houston, Texas, and the University of Miami, Miami, Florida. Written informed consent was obtained from parents or legal guardians, and assent was obtained from children when appropriate.

Subjects were recruited from the BCM Pediatric HIV Research Clinics/Texas Children's Hospital and from the University of Miami Pediatric HIV Research Clinic/Holtz Children's

Study population and demographics

Between 2004 and 2009, the study enrolled 38 subjects with HIV infection and 35 uninfected controls, 22 of whom had not been exposed to HIV perinatally, 11 who had been exposed, and 2 whose exposure status was unknown.

Of the 38 children with HIV, 26 were enrolled at TCH and 12 were enrolled at HCH. All controls were enrolled at TCH; patients at TCH and HCH did not differ demographically (data not shown). All participants completed the initial enrollment visit and associated studies at baseline.

Discussion

The present study of children with HIV infection revealed statistically significant direct and indirect relationships between HIV infection, intracellular cytokine production, sleep duration and efficiency, and neurocognitive and psychosocial function. Greater production of the pro-inflammatory cytokines IFN-γ, IL-12, and TNF-α was associated with alterations in sleep duration which in turn was associated with the ability of HIV-infected patients to perform on neurodevelopment and

Conflict of interest statement

The authors declare no conflicts of interest with respect to the contents of this manuscript.

Acknowledgments

We thank the following for their support of this study: National Institutes of Health National Heart, Lung & Blood Institute (grant RO1-HL075933); National Institute of Allergy and Infectious Diseases (grants P30 AI036211 and T32 AI007456); the General Clinical Research Center RR-00188 at Texas Children's Hospital; Texas Children's Hospital Immunology Research Fund; Christine Cambrice, RN, BSN, Michelle Del Ray, RN, Renee Ali, CCRP, Lawrence Angelina, BS, CPA, Lisa Himic, BA, Louis Pruitt,

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