The BET bromodomain inhibitor apabetalone induces apoptosis of latent HIV-1 reservoir cells following viral reactivation

• 来源期刊: 中国药理学报（英文版）
• 关键词: latent HIV-1 reservoirs latency reversing agent BET inhibitors apabetalone P-TEFb HIV eradication
• 年，卷（期）: 2019,（1）
• 页码范围: 98-110
• 页数: 13页
• 语种: 英文

摘要

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 Tatdependent 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.