Alterations of circadian rhythm and sleep by HIV protein Tat

As new therapies extend the life expectancy of HIV patients, disabling symptoms such as sleep and circadian rhythm disturbances become more apparent. The suprachiasmatic nucleus (SCN) of the hypothalamus is the central circadian clock that regulates sleep onset and synchronizes the circadian rhythms of peripheral organs to each other and to the environmental light-dark (LD) cycle. Light regulates the SCN via the retinohypothalamic tract (RHT), a direct neural projection from the eye to the SCN, by releasing the neurotransmitter glutamate (Glu). Although the neuropathogenesis of HIV-1 is complex, the viral protein Tat is thought to play an important role, because Tat can be secreted from infected cells to the extracellular space to affect neighboring cells and readily cross the blood brain barrier. Since Glu is the neurotransmitter of the RHT and Tat is known to affect neuronal function through its actions on Glu pathways, we studied the effect of Tat to the SCN. Our previous work showed that acute application of Tat directly to the SCN both in vitro and in vivo could reset the circadian rhythm, possibly through Tat-induced Glu release in the SCN. To assess the long-term effect of Tat on sleep and circadian rhythm, we used the tetracycline-dependent and GFAP specific Tat transgenic mice, which exhibited neuropathology similar to postmortem neuroAIDS patients (Kim et al 2003, Am J Pathol). RT-PCR confirmed Tat expression in the SCN following doxycycline diet.

The circadian rhythm of wheel running activity exhibited reduced motor activity, fragmented nocturnal running rhythm, as well as decoupled synchronization to the environmental LD cycle in the Tat mice, compared with wild type (WT) controls. Circadian clock gene profiling from the SCN of animals under LD cycle with real time PCR showed that the circadian rhythm of the mPer2 expression was out of phase with the LD cycle by about 9 hours, whereas the mPer1 expression was normal in the Tat mice. Long-term expression of Tat (up to 30 weeks with dox diet) resulted in reduced magnitude of light-induced phase shift in response to a light pulse at CT 16 in free running animals under constant darkness (DD). EEG analysis showed fragmented sleep and altered onset for both NREM and REM sleep in the Tat mice. Delta power analysis showed fragmented sleep and altered onset for both the NREM and REM sleep in the Tat mice. Delta power analysis showed reduced delta sleep in the Tat mice. Our data suggest that the Tat mice appear to have impaired light entrainment, possibly due to desensitized Glu transmission in the SCN following long term Tat exposure, and also exhibit altered sleep onset and poor sleep quality.

Finally the alterations in sleep and circadian rhythm in the Tat mice are comparable with previous findings in AIDS patients, as well as primate and feline neuroAIDS models.

Jing M. Ding1, Sarath Vijayakumar1, Vishnu Chintalgattu1, Mike Smith1, Daniel O. Lee1, 2, and Jidong Fang 3.
Departments of 1 Physiology and 2 Medicine, School of Medicine, East Carolina University, Greenville, NC, and 3 Department of Psychiatry, College of Medicine, Pennsylvania State University, Hershey, PA