Inhibition of the TRIM24 bromodomain reactivates latent HIV-1

• DOI: 10.1101/2022.06.16.496524
• Publication Date: 2022-06-17T18:00:13Z
• Authors: Riley M. Horvath; Zabrina L. Brumme; Ivan Sadowski
• Keywords: Provirus; Jurkat cells; Transcription

Abstract Expression of the HIV-1 genome by RNA Polymerase II is regulated at multiple steps, as are most cellular genes, including recruitment general transcription factors and control transcriptional elongation from core promoter. We recently discovered that tripartite motif protein TRIM24 recruited to Long Terminal Repeat (LTR) interaction with TFII-I causes stimulating association PTEF-b/ CDK9. Because required for stimulation LTR, we were surprised find IACS-9571, a specific inhibitor C-terminal bromodomain, induces provirus expression in otherwise untreated cells. IACS-9571 reactivates T cell lines bearing different models latency. Additionally, treatment this bromodomain encourages productive newly infected cells inhibits formation immediate latent transcriptionally repressed provirus. synergizes PMA, ionomycin, TNF-α PEP005 activate expression. Furthermore, co-treatment CD4 + individuals on antiretroviral therapy (ART) caused robust Notably, did not cause global activation cells; rather, it inhibited induction IL2 CD69 human PBMCs Jurkat treated or PMA. These observations indicate represents novel latency reversing agent (LRA), unlike other compounds activity, partial suppression while inducing