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

J. P. Clark, Christopher S. Sampair, Paulo Kofuji, Avindra Nath, Jian M. Ding

Research output: Contribution to journalArticle

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 (NG-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 ω-agatoxin IVA and 1 μM ω-conotoxin GIVA) and bafilomycin A, (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.

Original languageEnglish (US)
JournalAmerican Journal of Physiology - Regulatory Integrative and Comparative Physiology
Volume289
Issue number3 58-3
DOIs
StatePublished - Sep 2005

Fingerprint

Human Immunodeficiency Virus Proteins
Trans-Activators
Circadian Rhythm
Light
Suprachiasmatic Nucleus
N-Methyl-D-Aspartate Receptors
Circadian Clocks
Synaptic Transmission
Mammals
Agatoxins
Q-Type Calcium Channels
N-Type Calcium Channels
HIV
2-Amino-5-phosphonovalerate
Tetanus Toxin
Lentivirus
NG-Nitroarginine Methyl Ester
Tetrodotoxin
Calcium Channel Blockers
Patch-Clamp Techniques

Keywords

  • Glutamate
  • Human immunodeficiency virus
  • Phase shift

ASJC Scopus subject areas

  • Physiology

Cite this

HIV protein, transactivator of transcription, alters circadian rhythms through the light entrainment pathway. / Clark, J. P.; Sampair, Christopher S.; Kofuji, Paulo; Nath, Avindra; Ding, Jian M.

In: American Journal of Physiology - Regulatory Integrative and Comparative Physiology, Vol. 289, No. 3 58-3, 09.2005.

Research output: Contribution to journalArticle

@article{3f8dc3b4c58d4aed9b56fc9a96da3a06,
title = "HIV protein, transactivator of transcription, alters circadian rhythms through the light entrainment pathway",
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 (NG-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 ω-agatoxin IVA and 1 μM ω-conotoxin GIVA) and bafilomycin A, (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.",
keywords = "Glutamate, Human immunodeficiency virus, Phase shift",
author = "Clark, {J. P.} and Sampair, {Christopher S.} and Paulo Kofuji and Avindra Nath and Ding, {Jian M.}",
year = "2005",
month = "9",
doi = "10.1152/ajpregu.00179.2005",
language = "English (US)",
volume = "289",
journal = "American Journal of Physiology",
issn = "0363-6135",
publisher = "American Physiological Society",
number = "3 58-3",

}

TY - JOUR

T1 - HIV protein, transactivator of transcription, alters circadian rhythms through the light entrainment pathway

AU - Clark, J. P.

AU - Sampair, Christopher S.

AU - Kofuji, Paulo

AU - Nath, Avindra

AU - Ding, Jian M.

PY - 2005/9

Y1 - 2005/9

N2 - 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 (NG-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 ω-agatoxin IVA and 1 μM ω-conotoxin GIVA) and bafilomycin A, (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.

AB - 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 (NG-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 ω-agatoxin IVA and 1 μM ω-conotoxin GIVA) and bafilomycin A, (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.

KW - Glutamate

KW - Human immunodeficiency virus

KW - Phase shift

UR - http://www.scopus.com/inward/record.url?scp=23944521489&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=23944521489&partnerID=8YFLogxK

U2 - 10.1152/ajpregu.00179.2005

DO - 10.1152/ajpregu.00179.2005

M3 - Article

VL - 289

JO - American Journal of Physiology

JF - American Journal of Physiology

SN - 0363-6135

IS - 3 58-3

ER -