Circadian rhythms are physiological functions that manifest a 24-hr period, including sleep-wake cycle, body temperature, neuroendocrine and neuroimmune interactions. 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. A circadian clock located in the suprachiasmaticnucleus (SCN) of the hypothalamus regulates the circadian rhythms of all organ systems. We hypothesize that the alteration of sleep patterns and circadian rhythms in HIV infected patients may be caused by disrupting this central circadian clock. 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 and sleep during HIV infection. Our previous study showed that acute application of Tat directly to the SCN both in vitro and in vivo could reset the circadian clock (Clark et al 2005). To assess the long term effect of Tat to the sleep and circadian timing system, we used the tetracycline-dependent and brain (GFAP) specific Tat transgenic mice. RT-PCR confirmed Tat expression in the SCN following doxycycline diet. The alteration of circadian rhythm and sleep pattern in the Tat-expressing mouse is comparable to clinical findings, characterized with reduced motor activity and impaired synchronization to the environmental light dark cycle. EEG analysis showed altered delta power in the Tat mice. The EEG data recorded from the Tat mice are similar to findings in AIDS patients (Darko et al 1995;Polich et al 2000). Since little is known about viral- induced alteration of circadian rhythm and sleep at a cellular and molecular level, this research may yield novel understanding of viral neuropathogenesis and potentially lead to therapeutic approaches to circadian rhythm disorders experienced by HIV-infected patients.
Alteration of circadian rhythm and sleep occurs in AIDS patients with different disease stages and with a wide range of CD4 counts. Although the exact mechanism of HIV-1 neuropathogenesis remains poorly understood, viral proteins (gp41, gp120, and Tat) are thought to play a major role in the neural AIDS. Among these viral proteins, Tat is important because it can be secreted from infected cells to the extracellular space, subsequently affecting nearby neurons. Since our previous study demonstrated that Tat could reset the circadian clock in the brain, the suprachiasmatic nucleus (SCN), we hypothesize that the disruption of circadian rhythm and sleep during HIV infection could be a consequence of Tat on the SCN. To test our hypothesis, we used a transgenic mouse model that can selectively induce the expression of Tat in the brain when doxycycline is administered to the animals. RT-PCR confirmed Tat expression in the mouse SCN two weeks after feeding the animals with the doxycycline diet. Interestingly, the alteration of circadian rhythm in the Tat-expressing mouse is comparable to that found in the HIV-infected patients, characterized with reduced motor activity and impaired synchronization to the environmental light dark cycle. EEG analysis showed decreased delta power in the Tat transgenic mice compared to wild type mice.
