This subproject is one of many research subprojects utilizing the resources provided by a Center grant funded by NIH/NCRR. The subproject and investigator (PI) may have received primary funding from another NIH source, and thus could be represented in other CRISP entries. The institution listed is for the Center, which is not necessarily the institution for the investigator. The Baylor College of Medicine Pediatric HIV Research Center intends to pursue the inter-relationships of sleep, fatigue and HIV/AIDS (RFA-HL-04-010) in older children and adolescents infected with HIV-1. The Center will do so by exploring the molecular relationships between HIV-1 infection and homeostatic sleep-regulating cytokines, and hormones soluble tumor necrosis factor alpha receptor 1 (sTNF-aR1) and interleukin-6 (IL-6), growth hormone-releasing hormone (GHRH), and corticotropin-releasing hormone (CRH). This will be acomplished by repeat (12-month repeat) 24-hr studies of HIV-1 infected subjects and control subjects admitted to the General Clinical Research Center (GCRC) at Texas Children's Hospital. The hypothesis for this research project is that HIV-1 infection upregulates the secretion of sTNF-a R1, IL-6, GHRH, and CRH, producing a state of fatugue, sleepiness, and insomnia that, itself, forms an inflammatory immune response and spread of HIV-disease progression (as compared to a cytotoxic immune response that contains HIV-infection) and contributes to a decline in neurocognitive ability. Among the studies that will be used to validate this hypothesis are: 1. validated sleep questionnaires and actigraphy;2. peripheral blood measurements of sTNF-aR1, IL-6, GHRH, CRH, cortisol, lymphocytes, absolute and CD4+T-cell counts, interferon-gamma (IFN-y), interleukin-1 receptor antagonist (IL-1RA), IL-10, IL-2, HIV-1 RNA;and 3. neurocognitive assessments. Based upon preliminary observations, it is expected that there will be significant correlations between HIV-1 infected older children and adolescents with more progressive HIV-1 viral burden, and elevations in sTNF-a R1, IL-6, GHRH, and CRH. Also, TH1 cytotoxic cytokines (IFN-y, IL-12) would be expected to be lowered and anti-inflammatory cytokines (IL-10, IL-1RA) to be elevated. HIV-1 infected older children and adolescents with more progressive HIV-1 disease would be expected to have more documented sleep disorders and lower neurocognitive scores. This significance of these studies is that they will attempt to define the molecular connections between the neuroendocrine sleep-regulating cytokine and hormones (TNF-a R1, IL-6, GHRH, CRH) and the immune response, in particular, the shifting away from a cytotoxic response (IFN-y, IL-12). In addition, neurocognitive correlates will be made in patients with sleep disturbance and fatigue. Thus, these studies may help explain the effects of HIV-1 infection upon the sleep regulating pathways of the neuroendocrine-immune pathways that accelerate HIV-1 disease progression and contribute to the loss of neurocognitive function and general debilitation of children infected with HIV-1 perinatally or through risky adult-type behavior. 1. Children with more advanced HIV-1 disease progression will have more evidence of poor sleep habits, fatigue, and increased daytime sleepiness, as compared to control children. 2. Elevated plasma and peripheral blood monocuclear cell levels of sTNF-aR1, IL-6, and GHRH will be closely associated with high levels of anti-inflammatory cytokines (IL-1RA, IL-10) and markers of HIV-1 disease progression (low CD+4 T-cell count, high HIV-1 RNA level, low IFN-y, and IL-12 TH-1 cytokine levels). 3. HIV-1 infected children with fatigue, poor sleep habits, and altered sleep and HIV-1 disease cytokines will exhibit more severe neurocognitive and neurobehavioral deficits, evident in a faster decline in performance on repeated motor and mental tasks, and will have decreased consolidation of recent memory.
AIMS 4. Using validated sleep questionnaires and actigraphy measurements, assess the degree of abnormal sleeping pattersn, fatigue, and daytime sleepiness in HIV-1 infected children and control children. 5. Measure peripheral blood plasma, T-cell and monocyte levels of sleep-regulating cytokines and hormones (sTNF-aR1,IL-6, GHRH, CRH), pro-inflammatory cytokines (IL-1B, TNF-a), anti-inflammatory cytokines (IL-1RA, IL-10), and TH1 cytokines (IFN-y, IL012) in HIV-1 infected children and control children to determine the association between alterations in sleep-regulating cytokines and HIV-1 disease progression (CD4+ T-cell count, HIV-1 RNA level). 6. Perform neurocognitive and neuropsychological tests on the same cohorts of HIV-1 infected children and control children to dtermine if there is an association between lack of normal sleeping habits, neurocognitive/neuropsychological performance.
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