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. This study will explore the molecular relationships between HIV-1 infection and homeostatic sleep-regulating cytokines, and hormones soluble tumor necrosis factor alpha receptor I (sTNF-a RI) and interleukin-6 (IL-6), growth hormone-releasing hormone (GHRH), and corticotropin-releasing hormone (CRH). This will be accomplished 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 RI, IL-6, GHRH, and CRH, producing a state of fatigue, 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-aRI, IL-6, GHRH, CRH, cortisol, lymphocytes, absolute and CD4+ T-cell counts, interferon-gamma (IFN-g), interleukin-1 receptor antagonist (IL-1 RA), IL-10, IL-12, HIV-1 RNA; and 3) neurocognitive assessments. Based upon preliminary observations, it is expected that there will be significant correlations between HIV-1 viral burden, and elevations in sTNF-a RI, IL-6, GHRH, and CRH. Also, TH1 cytotoxic cytokines (IFN-g, 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 cytokines and hormones (TNF-a RI, IL-6, GHRH, CRH) and the immune response, in particular, the shifting away from a cytotoxic response (IFN-g, 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
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