Bromodomain and Extra-Terminal Inhibitor BMS-986158 Reverses Latent HIV-1 Infection In Vitro and Ex Vivo by Increasing CDK9 Phosphorylation and Recruitment.

Xu-Sheng Huang,Meng-Di Ma,Yong-Tang Zheng,Liu-Meng Yang,Mi Zhang,Xing-Qi Dong,Rong-Hua Luo,Guang-Hui Peng,Ren-Rong Tian

doi:10.3390/ph15030338

Abstract

Latent reservoir persistence remains a major obstacle for curing human immunodeficiency virus type 1 (HIV-1) infection. Thus, strategies for the elimination of latent HIV-1 are urgently needed. As a bromodomain and extra-terminal (BET) inhibitor, BMS-986158 has been used in clinical trials for advanced solid tumors and hematological malignancies. Here, we found that BMS-986158 reactivated latent HIV-1 in three types of HIV-1 latency cells in vitro, and in combination antiretroviral therapy (cART)-treated patient-derived peripheral blood mononuclear cells ex vivo, without influencing global immune cell activation. BMS-986158 reactivated latent HIV-1 by increasing phosphorylation of CDK9 at Thr186 and promoting recruitment of CDK9 and RNA polymerase II to the HIV-1 long terminal repeat in J-Lat cells. Furthermore, BMS-986158 exerted strong synergism in reactivating latent HIV-1 when combined with prostratin and vorinostat and enhanced the antiviral activity of anti-HIV-1 drugs. Finally, BMS-986158 showed antiviral activity in an HIV-1 acute infection model, possibly by arresting the cell cycle in infected cells. Thus, these results suggest that BMS-986158 is a potential candidate for AIDS/HIV-1 therapy.

Highlights

Acquired immunodeficiency syndrome (AIDS) is an incurable disease caused by human immunodeficiency virus (HIV) infection
Results showed that BMS-986158 reversed human immunodeficiency virus type 1 (HIV-1) latency dose dependently
Our results showed that BMS-986158 moderately down-regulated the expression of the CXCR4 and CCR5 co-receptors in the CD4+ T cells (Figure 2D,E), indicating that BMS-986158 does not increase potential de novo HIV-1 infection

Summary

Introduction

Acquired immunodeficiency syndrome (AIDS) is an incurable disease caused by human immunodeficiency virus (HIV) infection. Combination antiretroviral therapy (cART) can suppress HIV replication to undetectable levels and promote immune system reconstruction, the virus can persist in various cells and tissues of HIV-infected patients and may not be eliminated [1,2]. Latent reservoirs established in early infection, which can persist lifelong under ongoing cART, remain a huge obstacle for treatment of HIV infection [4]. The “shock and kill” strategy, which aims to reactivate and purge the latent reservoir with cART, has gained attention in recent years [5,6]. The first challenge of this strategy is to identify potent latency reversing agents (LRAs) to reactivate the latent virus. Many such agents have been investigated in vitro and ex vivo, with several reaching the clinical

Results

Discussion

Conclusion