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

作　　者：Xuan-xuan Zhang Jian Lin Tai-zhen Liang Heng Duan Xing-hua Tan Bao-min Xi Lin Li Shu-wen Liu 

机构地区：[1]Guangdong Provincial Key Laboratory of New Drug Screening,Guangzhou Key Laboratory of Drug Research for Emerging Virus Prevention and Treatment,State Key Laboratory of Organ Failure Research,School of Pharmaceutical Sciences,Southern Medical University,Guangzhou 510515,China [2]Department of Pharmacy,Stomatological Hospital of Southern Medical University and Guangdong Provincial Stomatological Hospital,Guangzhou 510280,China [3]Department of Infectious Disease,Guangzhou No 8 People's Hospital,Guangzhou 510060,China

出　　处：《Acta Pharmacologica Sinica》2019年第1期98-110,共13页中国药理学报（英文版）

基　　金：the Natural Science Foundation of China (81773787 to SL and 81673481 to LL);National Science and Technology Major Project (2018ZX10301101 to SL).

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.

关 键 词：LATENT HIV-1 reservoirs latency reversing agent BET inhibitors apabetalone P-TEFB HIV eradication. 

分 类 号：R[医药卫生]