Resveratrol inhibited Tat-induced HIV-1 LTR transactivation via NAD+-dependent SIRT1 activity

Aims: 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. Main 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. Key findings: 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. Significance: 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. (C) 2009 Elsevier Inc. All rights reserved.