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...
Saved in:
| Main Authors: | , , , , , , , , , , , |
|---|---|
| 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 |
| Tags: |
Add Tag
No Tags, Be the first to tag this record!
|
| _version_ | 1832592713330982912 |
|---|---|
| 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. |
| format | Article |
| id | doaj-art-5390f996c27f49f3abec55b1597aae84 |
| institution | Kabale University |
| issn | 1553-7366 1553-7374 |
| language | English |
| publishDate | 2024-09-01 |
| publisher | Public Library of Science (PLoS) |
| record_format | Article |
| series | PLoS Pathogens |
| 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 |
| work_keys_str_mv | AT williamjcisneros releaseofptefbfromthesuperelongationcomplexpromoteshiv1latencyreversal AT shimaahasoliman releaseofptefbfromthesuperelongationcomplexpromoteshiv1latencyreversal AT miriamwalter releaseofptefbfromthesuperelongationcomplexpromoteshiv1latencyreversal AT lacymsimons releaseofptefbfromthesuperelongationcomplexpromoteshiv1latencyreversal AT daphnecornish releaseofptefbfromthesuperelongationcomplexpromoteshiv1latencyreversal AT simonedefabritiis releaseofptefbfromthesuperelongationcomplexpromoteshiv1latencyreversal AT arielwhalle releaseofptefbfromthesuperelongationcomplexpromoteshiv1latencyreversal AT eunyoungkim releaseofptefbfromthesuperelongationcomplexpromoteshiv1latencyreversal AT stevenmwolinsky releaseofptefbfromthesuperelongationcomplexpromoteshiv1latencyreversal AT ramonlorenzoredondo releaseofptefbfromthesuperelongationcomplexpromoteshiv1latencyreversal AT alishilatifard releaseofptefbfromthesuperelongationcomplexpromoteshiv1latencyreversal AT juddfhultquist releaseofptefbfromthesuperelongationcomplexpromoteshiv1latencyreversal |