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TRANSLATIONAL PHYSIOLOGY

HIV protein, transactivator of transcription, alters circadian rhythms through the light entrainment pathway

¹Neuroscience Program and ²School of Dentistry, University of Minnesota, Minneapolis, Minnesota; ³Department of Neurology, Johns Hopkins University, Baltimore, Maryland; and ⁴Department of Physiology, Brody School of Medicine, East Carolina University, Greenville, North Carolina

Submitted 14 March 2005 ; accepted in final form 27 April 2005

ABSTRACT

Patients infected with the human immunodeficiency virus (HIV), and other mammals infected with related lentiviruses, exhibit fatigue, altered sleep patterns, and abnormal circadian rhythms. A circadian clock in the hypothalamic suprachiasmatic nucleus (SCN) temporally regulates these functions in mammals. We found that a secretary HIV transcription factor, transactivator of transcription (Tat), resets the murine circadian clock, in vitro and in vivo, at clinically relevant concentrations (EC₅₀ = 0.31 nM). This effect of Tat occurs only during the subjective night, when N-methyl-D-aspartate (NMDA) receptor [D-2-amino-5-phosphonovaleric acid (0.1 mM)] and nitric oxide synthase (N^G-nitro-L-arginine methyl ester, 0.1 mM) inhibitors block Tat-induced phase shifts. Whole cell recordings of SCN neurons within the brain slice revealed that Tat did not activate NMDA receptors directly but potentiated NMDA receptor currents through the enhancement of glutamate release. Consistent with this presynaptic mechanism, inhibitors of neurotransmission block Tat-induced phase shifts, such as tetrodotoxin (1 µM), tetanus toxin (1 µM), P/Q/N type-calcium channel blockers (1 µM -agatoxin IVA and 1 µM -conotoxin GIVA) and bafilomycin A₁ (1 µM). Thus the effect of Tat on the SCN may underlie lentiviral circadian rhythm dysfunction by operating as a disease-dependent modulator of light entrainment through the enhancement of excitatory neurotransmission.

glutamate; phase shift; human immunodeficiency virus

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