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

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

  • Pharmaceuticals (Basel). 2022 Mar 10;15(3):338. doi: 10.3390/ph15030338.
Xu-Sheng Huang 1 2,  Ren-Rong Tian 1,  Meng-Di Ma 1 2,  Rong-Hua Luo 1,  Liu-Meng Yang 1,  Guang-Hui Peng 3,  Mi Zhang 3,  Xing-Qi Dong 3,  Yong-Tang Zheng 1 2
Affiliations

Affiliations

  • 1 Key Laboratory of Bioactive Peptides of Yunnan Province/Key Laboratory of Animal Models and Human Disease Mechanisms of the Chinese Academy of Sciences, KIZ-CUHK Joint Laboratory of Bioresources and Molecular Research in Common Diseases, Center for Biosafety Mega-Science, Kunming Institute of Zoology, Chinese Academy of Sciences, Kunming 650223, China.
  • 2 University of Chinese Academy of Sciences, Beijing 100049, China.
  • 3 Yunnan Provincial Infectious Diseases Hospital/Yunnan Provincial Care Center for AIDS, Kunming 650301, China.
PMID: 35337136 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.

Keywords

BET; BMS-986158; HIV-1; latency reversing agent; latent reservoir.

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