TRIM24 controls induction of latent HIV-1 by stimulating transcriptional elongation

Abstract

Binding of USF1/2 and TFII-I (RBF-2) at conserved sites flanking the HIV-1 LTR enhancer is essential for reactivation from latency in T cells, with TFII-I knockdown rendering the provirus insensitive to T cell signaling. We identified an interaction of TFII-I with the tripartite motif protein TRIM24, and these factors were found to be constitutively associated with the HIV-1 LTR. Similar to the effect of TFII-I depletion, loss of TRIM24 impaired reactivation of HIV-1 in response to T cell signaling. TRIM24 deficiency did not affect recruitment of RNA Pol II to the LTR promoter, but inhibited transcriptional elongation, an effect that was associated with decreased RNA Pol II CTD S2 phosphorylation and impaired recruitment of CDK9. A considerable number of genomic loci are co-occupied by TRIM24/TFII-I, and we found that TRIM24 deletion caused altered T cell immune response, an effect that is facilitated by TFII-I. These results demonstrate a role of TRIM24 for regulation of transcriptional elongation from the HIV-1 promoter, through its interaction with TFII-I, and by recruitment of P-TEFb. Furthermore, these factors co-regulate a significant proportion of genes involved in T cell immune response, consistent with tight coupling of HIV-1 transcriptional activation and T cell signaling.

Release of P-TEFb from the Super Elongation Complex promotes HIV-1 latency reversal

“…Blocks to transcriptional elongation have been shown to contribute to HIV-1 latency maintenance in cells from virally suppressed people living with HIV (PLWH) (13, 14). The release of P-TEFb sequestration from BRD4 using bromodomain inhibitors (such as JQ1) has proven effective at reactivating viral gene expression in peripheral blood mononuclear cells (PBMCs) from these patients (54).…”

“…Blocks to transcriptional elongation are major contributors to establishing and maintaining HIV-1 latency (13, 14). After integration of the proviral DNA, RNA Polymerase II (RNA Pol II) is recruited to the transcription start site by transcription factors that bind cis- elements in the HIV-1 promoter region.…”

HIV-1 transcriptional modulation: novel host factors and prospective therapeutic strategies

“…However, Tat methylation and SMYD5 ubiquitination sites remain unknown, and additional work is needed to elucidate SMYD5 participation in Tat-transactivation of the HIV-1 LTR. Recently, the tripartite-motif containing protein 24 (TRIM24) was also found to interact with TFII-I [41 ▪ ]. This TF selectively regulates gene expression of TATA box-containing promoters and together with upstream stimulatory factor 1 (USF1) and USF2 plays a role during HIV-1 reactivation upon Jurkat T-cell activation [41 ▪ ,42–45].…”

“…Recently, the tripartite-motif containing protein 24 (TRIM24) was also found to interact with TFII-I [41 ▪ ]. This TF selectively regulates gene expression of TATA box-containing promoters and together with upstream stimulatory factor 1 (USF1) and USF2 plays a role during HIV-1 reactivation upon Jurkat T-cell activation [41 ▪ ,42–45]. TFII-I seems to recruit TRIM24 to promote transcription elongation through enhanced CDK9 and Ser2 RNAPII CTD phosphorylation [41 ▪ ].…”

“…This TF selectively regulates gene expression of TATA box-containing promoters and together with upstream stimulatory factor 1 (USF1) and USF2 plays a role during HIV-1 reactivation upon Jurkat T-cell activation [41 ▪ ,42–45]. TFII-I seems to recruit TRIM24 to promote transcription elongation through enhanced CDK9 and Ser2 RNAPII CTD phosphorylation [41 ▪ ]. Furthermore, inhibition of the TRIM24-C terminal bromodomain using the small molecule IACS-9571 [46,47], in combination with the PKC agonist PEP005 [48], promotes HIV-1 reactivation in primary CD4 + lymphocytes, supporting their potential use as latency reversing agents (LRAs) [49 ▪ ].…”