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)inh...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.展开更多
目的比较哮喘患者及健康对照外周血CD4+T细胞转录因子T-bet、GATA-3表达水平。方法选取新疆医科大学第六附属医院门诊及住院哮喘患者100例;同期健康志愿者100例;获取的外周血标本中的CD4+T淋巴细胞,是采用免疫磁珠法分离提取获得;而T-be...目的比较哮喘患者及健康对照外周血CD4+T细胞转录因子T-bet、GATA-3表达水平。方法选取新疆医科大学第六附属医院门诊及住院哮喘患者100例;同期健康志愿者100例;获取的外周血标本中的CD4+T淋巴细胞,是采用免疫磁珠法分离提取获得;而T-bet、GATA-3转录因子mRNA表达水平,其检测用SYBR Green I实时荧光定量法。结果T-bet基因mRNA表达含量在哮喘组中为(6.90±2.25),对照组中为(6.74±2.16)。与对照组相比,哮喘组表达含量较高,但差异无统计学意义(P>0.05)。GATA-3基因mRNA在哮喘中相对表达量为(4.22±2.03),健康对照组中相对表达量(3.15±2.22)。与对照组相比,哮喘组GATA-3mRNA明显较高,两组差异具有统计学意义(P<0.05)。结论支气管哮喘组Th2细胞转录因子GATA-3mRNA高表达,转录因子T-bet/GATA-3 mRNA的平衡破坏,进一步影响支气管哮喘的发生发展。展开更多
基金the Natural Science Foundation of China (81773787 to SL and 81673481 to LL)National Science and Technology Major Project (2018ZX10301101 to SL).
文摘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.
文摘目的比较哮喘患者及健康对照外周血CD4+T细胞转录因子T-bet、GATA-3表达水平。方法选取新疆医科大学第六附属医院门诊及住院哮喘患者100例;同期健康志愿者100例;获取的外周血标本中的CD4+T淋巴细胞,是采用免疫磁珠法分离提取获得;而T-bet、GATA-3转录因子mRNA表达水平,其检测用SYBR Green I实时荧光定量法。结果T-bet基因mRNA表达含量在哮喘组中为(6.90±2.25),对照组中为(6.74±2.16)。与对照组相比,哮喘组表达含量较高,但差异无统计学意义(P>0.05)。GATA-3基因mRNA在哮喘中相对表达量为(4.22±2.03),健康对照组中相对表达量(3.15±2.22)。与对照组相比,哮喘组GATA-3mRNA明显较高,两组差异具有统计学意义(P<0.05)。结论支气管哮喘组Th2细胞转录因子GATA-3mRNA高表达,转录因子T-bet/GATA-3 mRNA的平衡破坏,进一步影响支气管哮喘的发生发展。