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 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.
Clark
J P
JP
Dept. of Physiology, Brody School of Medicine, East Carolina University, 600 Moye Blvd., Greenville, NC 27858, USA.
Sampair
Christopher S
CS
Kofuji
Paulo
P
Nath
Avindra
A
Ding
Jian M
JM
D000200:Action Potentials / Q000187:drug effects; D000818:Animals; D002940:Circadian Rhythm / Q000187:drug effects / Q000502:physiology* / Q000528:radiation effects*; D015696:Gene Products, tat / Q000494:pharmacology / Q000502:physiology*; D018698:Glutamic Acid / Q000378:metabolism; D066298:In Vitro Techniques; D008027:Light; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D016194:Receptors, N-Methyl-D-Aspartate / Q000378:metabolism; D013493:Suprachiasmatic Nucleus / Q000187:drug effects / Q000502:physiology*; D009435:Synaptic Transmission / Q000187:drug effects / Q000502:physiology; D054322:tat Gene Products, Human Immunodeficiency Virus
D015696:Gene Products, tat; D016194:Receptors, N-Methyl-D-Aspartate; D054322:tat Gene Products, Human Immunodeficiency Virus; C470431:tat peptide (1-72), Human immunodeficiency virus 1; D018698:Glutamic Acid