Abstract
The persistence of latent HIV-1 reservoirs throughout combination antiretroviral therapy (cART) is a major barrier on the path to achieving a cure for AIDS. It has been shown that bromodomain and extra-terminal (BET) inhibitors could reactivate HIV-1 latency, but restrained from clinical application due to their toxicity and side effects. Thus, identifying a new type of BET inhibitor with high degrees of selectivity and safety is urgently needed. Apabetalone is a small-molecule selective BET inhibitor specific for second bromodomains, and has been evaluated in phase III clinical trials that enrolled patients with high-risk cardiovascular disorders, dyslipidemia, and low HDL cholesterol. In the current study, we examined the impact of apabetalone on HIV-1 latency. We showed that apabetalone (10−50 μmol/L) dose-dependently reactivated latent HIV-1 in 4 types of HIV-1 latency cells in vitro and in primary human CD4+ T cells ex vivo. In ACH2 cells, we further demonstrated that apabetalone activated latent HIV-1 through Tat-dependent P-TEFB pathway, i.e., dissociating bromodomain 4 (BDR4) from the HIV-1 promoter and recruiting Tat for stimulating HIV-1 elongation. Furthermore, we showed that apabetalone (10−30 μmol/L) caused dose-dependent cell cycle arrest at the G1/G0 phase in ACH2 cells, and thereby induced the preferential apoptosis of HIV-1 latent cells to promote the death of reactivated reservoir cells. Notably, cardiovascular diseases and low HDL cholesterol are known as the major side effects of cART, which should be prevented by apabetalone. In conclusion, apabetalone should be an ideal bifunctional latency-reversing agent for advancing HIV-1 eradication and reducing the side effects of BET inhibitors.
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Acknowledgements
We thank Dr. Shibo Jiang and Dr. Lu Lu at Fudan University, China, for generously providing HIV-1 latent cell models and reagents. This study was financially supported by grants from the Natural Science Foundation of China (81773787 to SL and 81673481 to LL) and National Science and Technology Major Project (2018ZX10301101 to SL).
Author contributions
XZ, LL, and SL conceived the project and wrote the manuscript. XZ, JL, and TL performed the experiments. HD and BX analyzed the data. XT provided the clinical samples. All authors reviewed the manuscript. LL and SL supervised the project and revised the manuscript.
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Zhang, Xx., Lin, J., Liang, Tz. et al. The BET bromodomain inhibitor apabetalone induces apoptosis of latent HIV-1 reservoir cells following viral reactivation. Acta Pharmacol Sin 40, 98–110 (2019). https://doi.org/10.1038/s41401-018-0027-5
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DOI: https://doi.org/10.1038/s41401-018-0027-5
