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

The persistence of HIV-1 in long-lived latent reservoirs during suppressive antiretroviral therapy (ART) remains one of the principal barriers to a functional cure. Blocks to transcriptional elongation play a central role in maintaining the latent state, and several latency reversal strategies focus...

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Main Authors: William J Cisneros, Shimaa H A Soliman, Miriam Walter, Lacy M Simons, Daphne Cornish, Simone De Fabritiis, Ariel W Halle, Eun-Young Kim, Steven M Wolinsky, Ramon Lorenzo-Redondo, Ali Shilatifard, Judd F Hultquist
Format: Article
Language:English
Published: Public Library of Science (PLoS) 2024-09-01
Series:PLoS Pathogens
Online Access:https://doi.org/10.1371/journal.ppat.1012083
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author William J Cisneros
Shimaa H A Soliman
Miriam Walter
Lacy M Simons
Daphne Cornish
Simone De Fabritiis
Ariel W Halle
Eun-Young Kim
Steven M Wolinsky
Ramon Lorenzo-Redondo
Ali Shilatifard
Judd F Hultquist
author_facet William J Cisneros
Shimaa H A Soliman
Miriam Walter
Lacy M Simons
Daphne Cornish
Simone De Fabritiis
Ariel W Halle
Eun-Young Kim
Steven M Wolinsky
Ramon Lorenzo-Redondo
Ali Shilatifard
Judd F Hultquist
author_sort William J Cisneros
collection DOAJ
description The persistence of HIV-1 in long-lived latent reservoirs during suppressive antiretroviral therapy (ART) remains one of the principal barriers to a functional cure. Blocks to transcriptional elongation play a central role in maintaining the latent state, and several latency reversal strategies focus on the release of positive transcription elongation factor b (P-TEFb) from sequestration by negative regulatory complexes, such as the 7SK complex and BRD4. Another major cellular reservoir of P-TEFb is in Super Elongation Complexes (SECs), which play broad regulatory roles in host gene expression. Still, it is unknown if the release of P-TEFb from SECs is a viable latency reversal strategy. Here, we demonstrate that the SEC is not required for HIV-1 replication in primary CD4+ T cells and that a small molecular inhibitor of the P-TEFb/SEC interaction (termed KL-2) increases viral transcription. KL-2 acts synergistically with other latency reversing agents (LRAs) to reactivate viral transcription in several cell line models of latency in a manner that is, at least in part, dependent on the viral Tat protein. Finally, we demonstrate that KL-2 enhances viral reactivation in peripheral blood mononuclear cells (PBMCs) from people living with HIV (PLWH) on suppressive ART, most notably in combination with inhibitor of apoptosis protein antagonists (IAPi). Taken together, these results suggest that the release of P-TEFb from cellular SECs may be a novel route for HIV-1 latency reactivation.
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spelling doaj-art-5390f996c27f49f3abec55b1597aae842025-01-21T05:30:55ZengPublic Library of Science (PLoS)PLoS Pathogens1553-73661553-73742024-09-01209e101208310.1371/journal.ppat.1012083Release of P-TEFb from the Super Elongation Complex promotes HIV-1 latency reversal.William J CisnerosShimaa H A SolimanMiriam WalterLacy M SimonsDaphne CornishSimone De FabritiisAriel W HalleEun-Young KimSteven M WolinskyRamon Lorenzo-RedondoAli ShilatifardJudd F HultquistThe persistence of HIV-1 in long-lived latent reservoirs during suppressive antiretroviral therapy (ART) remains one of the principal barriers to a functional cure. Blocks to transcriptional elongation play a central role in maintaining the latent state, and several latency reversal strategies focus on the release of positive transcription elongation factor b (P-TEFb) from sequestration by negative regulatory complexes, such as the 7SK complex and BRD4. Another major cellular reservoir of P-TEFb is in Super Elongation Complexes (SECs), which play broad regulatory roles in host gene expression. Still, it is unknown if the release of P-TEFb from SECs is a viable latency reversal strategy. Here, we demonstrate that the SEC is not required for HIV-1 replication in primary CD4+ T cells and that a small molecular inhibitor of the P-TEFb/SEC interaction (termed KL-2) increases viral transcription. KL-2 acts synergistically with other latency reversing agents (LRAs) to reactivate viral transcription in several cell line models of latency in a manner that is, at least in part, dependent on the viral Tat protein. Finally, we demonstrate that KL-2 enhances viral reactivation in peripheral blood mononuclear cells (PBMCs) from people living with HIV (PLWH) on suppressive ART, most notably in combination with inhibitor of apoptosis protein antagonists (IAPi). Taken together, these results suggest that the release of P-TEFb from cellular SECs may be a novel route for HIV-1 latency reactivation.https://doi.org/10.1371/journal.ppat.1012083
spellingShingle William J Cisneros
Shimaa H A Soliman
Miriam Walter
Lacy M Simons
Daphne Cornish
Simone De Fabritiis
Ariel W Halle
Eun-Young Kim
Steven M Wolinsky
Ramon Lorenzo-Redondo
Ali Shilatifard
Judd F Hultquist
Release of P-TEFb from the Super Elongation Complex promotes HIV-1 latency reversal.
PLoS Pathogens
title Release of P-TEFb from the Super Elongation Complex promotes HIV-1 latency reversal.
title_full Release of P-TEFb from the Super Elongation Complex promotes HIV-1 latency reversal.
title_fullStr Release of P-TEFb from the Super Elongation Complex promotes HIV-1 latency reversal.
title_full_unstemmed Release of P-TEFb from the Super Elongation Complex promotes HIV-1 latency reversal.
title_short Release of P-TEFb from the Super Elongation Complex promotes HIV-1 latency reversal.
title_sort release of p tefb from the super elongation complex promotes hiv 1 latency reversal
url https://doi.org/10.1371/journal.ppat.1012083
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