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. 2021 Jan 7;18:3. doi: 10.1186/s12977-020-00547-9

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© The Author(s) 2021

Open AccessThis article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons licence, and indicate if changes were made. The images or other third party material in this article are included in the article's Creative Commons licence, unless indicated otherwise in a credit line to the material. If material is not included in the article's Creative Commons licence and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this licence, visit http://creativecommons.org/licenses/by/4.0/. The Creative Commons Public Domain Dedication waiver (http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated in a credit line to the data.

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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