Fig. 2

A proposed model for the distinct effects of ZL0580 and JQ1 on BRD4 PPI and Tat-mediated HIV transcription elongation. a BRD4 inhibition by JQ1. In the absence of JQ1 (left), BRD4 competes with HIV Tat for cellular p-TEFb/CDK9 and thereby suppresses Tat-SEC interaction. JQ1 antagonizes this effect of BRD4 by displacing it from chromatin (disrupted BRD4-Ac-histone interaction) and promoting the formation of a functional Tat-SEC (CDK9/Cyclin T1/ELL2). Tat-SEC leads to RNAPII phosphorylation and productive HIV transcriptional elongation (based on Li et al. [25]). b BRD4 inhibition by ZL0580. ZL0580 induces a distinct effect from JQ1. By targeting the non-KAc site on BRD4, ZL0580 does not disrupt BRD4-Ac-histone interaction (no displacement of BRD4 from chromatin) but promotes BRD4 interaction with p-TEFb/CDK9, leading to competitive reduction in Tat binding to p-TEFb/CDK9. In addition, ZL0580 treatment also down-regulates ELL2 protein by reducing its protein stability. Reduced Tat-CDK9 binding and down-regulated ELL2 together lead to reduced RNAP phosphorylation at the HIV LTR and abortive HIV transcription elongation