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

Horvath, Riley; Dahabieh, Matthew S.; Malcolm, Tom; Sadowski, Ivan

doi:10.21203/rs.3.rs-1357296/v1

Cited by 5 publications

(47 citation statements)

References 50 publications

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“…8D, RBE1). These results are consistent with our previous observations indicating that recruitment of TRIM24 to the HIV-1 LTR causes enhanced recruitment of pTEF-b/ Cdk9, which promotes RNAPII CTD S2 phosphorylation and elongation of transcription [18].…”

Section: Iacs-9571 Stimulates Hiv-1 Transcriptional Elongation Our Pr...supporting

confidence: 94%

“…Consistent with our previous results indicating that TRIM24 is required for reactivation of latent HIV-1 [18] we found that cells treated with concentrations of dTRIM24 that reduce TRIM24 protein levels also displayed a corresponding decrease in expression of the 5' LTR dsRed reporter in these cells (Fig. 5C).…”

Section: Protac-induced Degradation Of Trim24 Inhibits Hiv-1 Expressionsupporting

confidence: 92%

“…6A, B) in combination with an HIV-1 LTR-luciferase reporter gene. Using this assay, we have previously demonstrated that the effect of TRIM24 for activation of HIV-1 expression does not require the viral transactivator TAT [18]. As with previous experiments, co-transfection of WT TRIM24 expression plasmid causes ~3 fold stimulation of the HIV-1 luciferase expression (Fig.…”

Section: The C-terminal Trim24 Bromodomain Is Dispensable For Activat...supporting

confidence: 74%

“…The TRIM24 bromodomain inhibitor IACS-9571 promotes HIV-1 expression. We previously discovered that TRIM24 is recruited to the HIV-1 LTR by interaction with TFII-I, and this causes enhanced elongation from the HIV-1 LTR through elevated CDK9 recruitment and RNA Pol II CTD S2 phosphorylation [18]. Importantly, Jurkat cell lines bearing TRIM24 gene knockouts are defective for reactivation of latent HIV-1 in response to T cell signaling.…”

Section: Resultsmentioning

confidence: 99%

“…Reactivation of HIV-1 expression in response to TCR signaling requires multiple factors specifically bound to the 5' LTR, including TFII-I which is constitutively associated with two highly conserved cis-elements flanking the LTR enhancer region in association with USF1/2 [16] [17]. We discovered that TFII-I recruits the coactivator protein Tripartite-Motif containing protein 24 (TRIM24) to the LTR, and this interaction promotes transcriptional elongation from the LTR core promoter by RNA Polymerase II [18], an effect that is associated with enhanced recruitment of CDK9 and increased RNA Pol II CTD on serine 2 phosphorylation. These observations indicate that TRIM24 may function as a transcriptional coactivator by promoting recruitment of P-TEFb.…”

Section: Introductionmentioning

confidence: 99%

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Inhibition of the TRIM24 bromodomain reactivates latent HIV-1

Horvath

Brumme

Sadowski

2022

Preprint

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

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Section: Iacs-9571 Stimulates Hiv-1 Transcriptional Elongation Our Pr...supporting

confidence: 94%

Section: Protac-induced Degradation Of Trim24 Inhibits Hiv-1 Expressionsupporting

confidence: 92%

Section: The C-terminal Trim24 Bromodomain Is Dispensable For Activat...supporting

confidence: 74%

Section: Resultsmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

See 3 more Smart Citations

Inhibition of the TRIM24 bromodomain reactivates latent HIV-1

Horvath

Brumme

Sadowski

2022

Preprint

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Inhibition of the TRIM24 bromodomain reactivates latent HIV-1

Horvath

Brumme

Sadowski

2023

Sci Rep

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CDK8 inhibitors antagonize HIV-1 reactivation and promote provirus latency in T cells

Horvath¹,

Brumme²,

Sadowski³

2023

Preprint

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Latent HIV-1 provirus represents a barrier towards a cure for infection, but is dependent upon the host RNA Pol II machinery for expression. We find that inhibitors of the RNA Pol II mediator kinases CDK8/19, Senexin A and BRD6989, inhibit induction of HIV-1 expression in response to latency reversing agents and T cell signaling agonists. These inhibitors were found to impair recruitment of RNA Pol II to HIV-1 LTR. HIV-1 expression in response to several latency reversal agents was impaired upon disruption of CDK8 by shRNA or gene knockout. However, the effects of CDK8 depletion did not entirely mimic CDK8/19 kinase inhibition suggesting that the mediator kinases are not functionally redundant. Furthermore, treatment of CD4+ PBMCs isolated from people living with HIV-1 and who are receiving ART with Senexin A inhibited induction of virus replication in response to T cell stimulation by PMA and ionomycin. These observations indicate that the mediator kinases CDK8 and CDK19, play a significant role for regulation of HIV-1 transcription, and that small molecule inhibitors of these enzymes may contribute to therapies designed to promote deep latency involving the durable suppression of provirus expression.

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

Cited by 5 publications

References 50 publications

Inhibition of the TRIM24 bromodomain reactivates latent HIV-1

Inhibition of the TRIM24 bromodomain reactivates latent HIV-1

Inhibition of the TRIM24 bromodomain reactivates latent HIV-1

CDK8 inhibitors antagonize HIV-1 reactivation and promote provirus latency in T cells

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