Circadian rhythms are physiological functions that manifest a 24-hour period, including sleep-wake cycle, body temperature, cognitive performances, neuroendocrine and neuroimmune interactions. Under pathological conditions, these bodily rhythms are often altered. Healthy individuals have a robust circadian oscillation of circulating lymphocytes with the peak at night, but this circadian rhythm is diminished in HIV-infected patients. In fact, disruption of sleep patterns and circadian rhythms are among the most common disorders in the early stages of HIV infection, tong before the onset of AIDS. A circadian clock located in the suprachiasmaticnucleus (SCN) of the hypothalamus regulates the circadian rhythms of all organ systems. When the SCN is ablated, the circadian rhythms are diminished. We hypothesize that the alteration of sleep patterns and circadian rhythms in HIV infected patients may be caused by disrupting this central circadian pacemaker. HIV-1 infection has been associated with a variety of neurological disorders. Although the neuropathogenesis of HIV-1 is complex, the viral protein Tat appears to play an important role. The SCN is located in the base on the third cerebral ventricle surrounded by the hypothalamic circumventricular organs (CVO). The CVOs are among the most permeable structures in the brain. Since Tat can be secreted to the circulation from infected cells and Tat can readily cross the blood brain barrier, we hypothesize that the SCN may be among the earliest target of Tat. Although the exact mechanism by which HIV-1 infection affects neuronal function remains unknown, Tat may play a pivotal role in the alteration of circadian rhythms in the early stages of HIV infection. This proposal will investigate the role of Tat protein in the disruption of circadian rhythm using in vitro SCN brain slice) and in vivo routine models to study the mechanisms of circadian clock resetting by Tat. Our preliminary data suggest that Tat reset the circadian clock via a glutamate receptor mediated signaling pathway. Since little is known about viral-induced alteration of circadian rhythms at a cellular and molecular level, this research will yield novel understanding of viral neuropathogenesis and in the long-term may lead to therapeutic approaches to circadian rhythm disorders experienced by HIV-infected patients.
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