{"database":"biostudies-literature","file_versions":[],"scores":null,"additional":{"omics_type":["Unknown"],"submitter":["Cisneros WJ"],"funding":["NIAID NIH HHS","NIGMS NIH HHS"],"pubmed_abstract":["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 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."],"journal":["bioRxiv : the preprint server for biology"],"pagination":["2024.03.01.582881"],"full_dataset_link":["https://www.ebi.ac.uk/biostudies/studies/S-EPMC10925308"],"repository":["biostudies-literature"],"pubmed_title":["Release of P-TEFb from the Super Elongation Complex promotes HIV-1 latency reversal."],"pmcid":["PMC10925308"],"funding_grant_id":["R21 AI174864","R01 AI167778","R56 AI174877","R01 AI150998","U54 AI170792","R01 AI150455","T32 GM008061","R01 AI176599","R01 AI165236","P30 AI117943"],"pubmed_authors":["Kim EY","Shilatifard A","Wolinsky SM","Hultquist JF","Halle AW","Cisneros WJ","Simons LM","Walter M","Soliman SHA","Cornish D"],"additional_accession":[]},"is_claimable":false,"name":"Release of P-TEFb from the Super Elongation Complex promotes HIV-1 latency reversal.","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 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.","dates":{"release":"2024-01-01T00:00:00Z","publication":"2024 Mar","modification":"2025-05-18T12:53:59.108Z","creation":"2025-05-18T12:53:59.108Z"},"accession":"S-EPMC10925308","cross_references":{"pubmed":["38464055"],"doi":["10.1101/2024.03.01.582881"]}}