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

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 ma...

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Bibliographic Details
Published in:	American journal of physiology. Regulatory, integrative and comparative physiology Vol. 289; no. 3; p. R656
Main Authors:	Clark, 3rd, J P, Sampair, Christopher S, Kofuji, Paulo, Nath, Avindra, Ding, Jian M
Format:	Journal Article
Language:	English
Published:	United States 01-09-2005
Subjects:	Action Potentials - drug effects Animals Circadian Rhythm - drug effects Circadian Rhythm - physiology Circadian Rhythm - radiation effects Gene Products, tat - pharmacology Gene Products, tat - physiology Glutamic Acid - metabolism In Vitro Techniques Light Male Mice Mice, Inbred C57BL Receptors, N-Methyl-D-Aspartate - metabolism Suprachiasmatic Nucleus - drug effects Suprachiasmatic Nucleus - physiology Synaptic Transmission - drug effects Synaptic Transmission - physiology tat Gene Products, Human Immunodeficiency Virus
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Summary:	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 (EC(50) = 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 microM), tetanus toxin (1 microM), P/Q/N type-calcium channel blockers (1 microM omega-agatoxin IVA and 1 microM omega-conotoxin GIVA) and bafilomycin A(1) (1 microM). 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.
ISSN:	0363-6119
DOI:	10.1152/ajpregu.00179.2005