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Resveratrol Promotes HIV-1 Tat Accumulation via AKT/FOXO1 Signaling Axis and Potentiates Vorinostat to Antagonize HIV-1 Latency

[ Vol. 19 , Issue. 3 ]

Author(s):

Zeming Feng, Zhengrong Yang, Xiang Gao, Yuhua Xue and Xiaohui Wang*   Pages 238 - 247 ( 10 )

Abstract:


Background: The latent reservoir of HIV-1 is a major barrier to achieving the eradication of HIV-1/AIDS. One strategy is termed “shock and kill”, which aims to awaken the latent HIV-1 using latency reversing agents (LRAs) to replicate and produce HIV-1 particles. Subsequently, the host cells containing HIV-1 can be recognized and eliminated by the immune response and anti-retroviral therapy. Although many LRAs have been found and tested, their clinical trials were dissatisfactory.

Objective: To aim of the study was to investigate how resveratrol reactivates silent HIV-1 transcription and assess if resveratrol could be a candidate drug for the “shock” phase in “shock and kill” strategy.

Methods: We used established HIV-1 transcription cell models (HeLa-based NH1 and NH2 cells) and HIV-1 latent cell models (J-Lat A72 and Jurkat 2D10 cells). We performed resveratrol treatment on these cell lines and studied the mechanism of how resveratrol stimulates HIV-1 gene transcription. We also tested resveratrol’s bioactivity on primary cells isolated from HIV-1 latent infected patients.

Results: Resveratrol promoted HIV-1 Tat protein levels, and resveratrol-induced Tat promotion was found to be dependent on the AKT/FOXO1 signaling axis. Resveratrol could partially dissociate P-TEFb (Positive Transcription Elongation Factor b) from 7SK snRNP (7SK small nuclear Ribonucleoprotein) and promote Tat-SEC (Super Elongation Complex) interaction. Preclinical studies showed that resveratrol potentiated Vorinostat to awaken HIV-1 latency in HIV-1 latent infected cells isolated from patients.

Conclusion: We found a new mechanism of resveratrol stimulating the production of HIV-1. Resveratrol could be a promising candidate drug to eradicate HIV-1 reservoirs.

Keywords:

HIV-1, Reservoirs, Resveratrol, HIV-1 Tat, AKT/FOXO1, P-TEFb, Super Elongation Complex.

Affiliation:

Shenzhen Center for Disease Control and Prevention, Shenzhen, Shenzhen Center for Disease Control and Prevention, Shenzhen, School of Pharmaceutical Sciences, Xiamen University, Xiamen, Fujian, School of Pharmaceutical Sciences, Xiamen University, Xiamen, Fujian, Shenzhen Center for Disease Control and Prevention, Shenzhen



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