Hong-Sheng Zhang1, Yue Zhou, Meng-Ran Wu, Hong-Sen Zhou, Fei Xu. 1. 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
Abstract
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.
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.
Authors: Christine L Clouser; Jay Chauhan; Matthew A Bess; Jessica L van Oploo; Ding Zhou; Sarah Dimick-Gray; Louis M Mansky; Steven E Patterson Journal: Bioorg Med Chem Lett Date: 2012-09-06 Impact factor: 2.823
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