Tissues of the immune and nervous systems are the primary targets of the human immunodeficiency virus (HIV). Sleep, a definable behavior, is regulated by interactions between neural and biochemical mechanisms, and is altered during viral infections, including HIV. It is estimated that as many as 60% of all HIV-infected individuals experience debilitating daytime fatigue and sleepiness. In addition, polysomnographic studies conducted on HIV-infected individuals indicate that nighttime sleep is altered. These alterations occur during chronic HIV infection, prior to the onset of AIDS, and in the absence of substance abuse or psychiatric symptoms associated with anxiety or depression. The precise mechanisms whereby HIV alters sleep are not known. In spite of HIV's inability to infect rodent cells, other laboratories have demonstrated the utility of rodent models for the study of cytokine actions and neurologic effects. The investigators have found, in a rat model of sleep, that HIV products induce alterations in sleep in a manner resembling those observed during HIV infection. Furthermore, in the investigators' model, HIV products increase cytokine mRNA expression within the rat central nervous system (CNS). HIV enters the CNS shortly after infection; cytokine concentrations, including the somnogenic cytokines interleukin-1 (IL-1) and tumor necrosis factor (TNF), are elevated within the CNS during all stages of HIV infection. The investigators hypothesize that altered sleep during HIV infection is due, in part, to HIV-induced increases within the CNS in concentrations of cytokines that enhance sleep (e.g. IL-1, TNF) as well as those that suppress sleep (e.g. IL-1 receptor antagonist (IL-1ra) and IL-10). The investigators will test this working hypothesis by: determining the components of HIV capable of altering sleep (i.e. HIV envelope glycoproteins [gps]), and by elucidating the roles of IL-1, TNF, IL-1ra, and IL-10 in responses to HIV and HIV gps. Finally, they will determine changes in cytokine mRNA expression in brain regions important for the regulation of sleep, in response to the HIV gps. They will use rats instrumented with EEG electrodes, and chronic guide cannulae directed into lateral cerebral ventricles. Sleep-wake activity, and changes in cytokine mRNA expression in the CNS, will be determined after administration of HIV or HIV gps. These experiments should show not only the extent to which cytokines within the CNS contribute to HIV-induced alterations in sleep, but may also suggest new therapeutic approaches for the debilitating symptoms of fatigue and sleepiness that occur during AIDS.

National Institute of Health (NIH)
National Institute of Mental Health (NIMH)
Research Project (R01)
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Special Emphasis Panel (ZMH1-BRB-T (M5))
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Joseph, Jeymohan
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University of Michigan Ann Arbor
Schools of Medicine
Ann Arbor
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