Resveratrol inhibited Tat-induced HIV-1 LTR transactivation via NAD(+)-dependent SIRT1 activity.
OBJECTIVE
Tat protein plays a pivotal role in both the human immunodeficiency virus type 1 (HIV-1) replication cycle and the pathogenesis of HIV-1 infection. Sirtuins 1 (SIRT1) is a possible candidate for redox modulation because its activity is regulated by nicotinamide adenine dinucleotide (NAD(+)) or NAD(+)/NADH ratio. The aim of the present study was to determine whether the redox status and SIRT1 expression are related to HIV-1 Tat protein-induced transactivation.


METHODS
HeLa-CD4-long terminal repeat (LTR)-beta-gal (MAGI) cells were transfected with Tat plasmid. Tat-induced HIV-1 LTR transactivation was determined by MAGI cell assay. The NAD(+) or NADH levels and SIRT1 activity were measured. In addition, the protein expression of SIRT1 was assayed by western blotting.


RESULTS
Pretreatment with resveratrol increased intracellular NAD(+) levels and SIRT1 protein expression after Tat plasmid transfection in a concentration-dependent manner. Pretreatment with resveratrol attenuated Tat-induced HIV-1 transactivation in MAGI cells. These effects of resveratrol were largely abolished by knockdown of SIRT1 by short interfering RNA (siRNA). Pretreatment with nicotinamide, a SIRT1 inhibitor, potentiated Tat-induced HIV-1 transactivation in MAGI cells, and overexpression of SIRT1 attenuated Tat-induced HIV-1 transcription in MAGI cells.


CONCLUSIONS
Inhibition of SIRT1 activity by Tat is considered a critical step of Tat transactivation. Resveratrol and related compounds represent potential candidates for novel anti-HIV therapeutics.
Zhang
Hong-Sheng
HS
Department of Virology and Pharmacology, College of Life Science and Bioengineering, Beijing University of Technology, District of Chaoyang, Beijing 100124, China. zhanghs@bjut.edu.cn
Zhou
Yue
Y
Wu
Meng-Ran
MR
Zhou
Hong-Sen
HS
Xu
Fei
F
D000972:Antineoplastic Agents, Phytogenic / Q000494:pharmacology*; D015153:Blotting, Western; D016325:HIV Long Terminal Repeat; D015497:HIV-1; D006367:HeLa Cells; D006801:Humans; D009243:NAD / Q000378:metabolism* / Q000502:physiology; D000077185:Resveratrol; D020133:Reverse Transcriptase Polymerase Chain Reaction; D056564:Sirtuin 1; D037761:Sirtuins / Q000037:antagonists & inhibitors / Q000378:metabolism*; D013267:Stilbenes / Q000494:pharmacology*; D015533:Transcriptional Activation / Q000187:drug effects*; D014779:Virus Replication; D054322:tat Gene Products, Human Immunodeficiency Virus / Q000378:metabolism*
D000972:Antineoplastic Agents, Phytogenic; D013267:Stilbenes; D054322:tat Gene Products, Human Immunodeficiency Virus; D009243:NAD; C447939:SIRT1 protein, human; D056564:Sirtuin 1; D037761:Sirtuins; D000077185:Resveratrol