The BET Bromodomain Inhibitor JQ1 Activates Latent HIV Transcriptional Activation Through HSP90-CDC37-CDK9 Complex

Acquired Immunodeficiency Syndrome(AIDS),caused by Human immuno-deficiency virus(HIV),is a contagious disease destroying human immune system.In clinical application,HIV virus cann't be eliminated by HARRT.The reason for its faiure to cure AIDS completely lies in the presence of latent HIV pool.A therapy,named"Shock and Kill",is aimed to find some latency reversing agents(LRAs)to activate latent HIV and to combine HARRT(Highly Active Antiretroviral Therapy)to kill new virus.According to the mechanisms of latent HIV formation,some LRAs acting on different ways and different targets are being discovered and studied,such as HADC inhibitor SAHA,PKC activator Prostratin and BET inhibitor JQ1.In this research,HSP90-CDC37-CDK9 complex plays an important role in regulating JQ1-induced latent HIV transcription.The main research contents are summarized as below:(1)Based on SILAC,JQ1 promotes combination between more HSP90-CDC37 complex;(2)More HSP90-CDC37 complex associates with CDK9 in a time-and dose-dependent manner under JQ1;(3)Another bromodomain inhibitor iBET-151 also increases combination between more HSP90-CDC37 and CDK9;(4)Inhibition of CDK9?Inhibition of HSP90 and knocking down HSP90 or knocking down CDC37 decreases the latent HIV reactivation of JQ1;(5)Stability of HSP90-CDC37-CDK9 complex is essential for JQ1's activity;(6)Inhibiting or knocking down HSP90 and CDC37 can reduce the function of JQ1-induced latent HIV transcription by formating 7SKsnRNP complex that includes more inactive CDK9;(7)HSF1 recruits more HSP90-CDK9 complex to participate JQ1-induced latent HIV-1 expression through interacting with HIV LTR promoter.Studying that the bromodomain inhibitor JQ1 resverses HIV latency through HSP90-CDC37-CDK9 complex,not only provides some evidences for the comlexity of JQ1's mechanism about inducing HIV transcription,but also gives theoretical basis for studying the mechanism of other LRAs.And for clinical study,this research has scientific significance and application value.