“Locking” CDK9 inhibition by activating integrator function in HIV transcription
Abstract
The positive transcription elongation factor b (P-TEFb) is a critical host factor for HIV transcription, yet pharmacological inhibition of its CDK9 subunit yields transient suppression with cytotoxicity. We identify that the integrator-PP2A complex enhances the potency and durability of CDK9 inhibition without added toxicity. Activation of PP2A with the small-molecule SMAP-2, combined with a low dose of the CDK9 inhibitor AZD4573, suppresses HIV transcription in CD4⁺ T cells, persisting for 7 days after drug withdrawal. Mechanistically, the drug combination increases integrator recruitment and repressive chromatin marks, decreases RNA polymerase II occupancy and C-terminal domain (CTD) phosphorylation at HIV promoter, and reduces short and long HIV transcripts, without global T cell activation, proliferation or broad transcriptome changes. The drug combination's HIV-inhibiting effect is somewhat resistant against elevated HIV activity in the presence of cocaine or morphine. These findings reveal cooperative P-TEFb inhibition and integrator activation as a promising strategy for durable HIV silencing.
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BibTeX
@article{li2026locking,
title = {{“Locking” CDK9 inhibition by activating integrator function in HIV transcription}},
author = {Zichong Li and Francisco J. Zapatero-Belinchón and Patrik Geleziunas and Melanie Ott},
journal = {iScience},
year = {2026},
month = oct,
doi = {10.1016/j.isci.2026.117894},
url = {https://www.cell.com/iscience/fulltext/S2589-0042(26)03277-3},
note = {CC BY 4.0},
}
RIS
TY - JOUR
TI - “Locking” CDK9 inhibition by activating integrator function in HIV transcription
AU - Zichong Li
AU - Francisco J. Zapatero-Belinchón
AU - Patrik Geleziunas
AU - Melanie Ott
PY - 2026
DA - 2026/10/17
JO - iScience
DO - 10.1016/j.isci.2026.117894
UR - https://www.cell.com/iscience/fulltext/S2589-0042(26)03277-3
AB - The positive transcription elongation factor b (P-TEFb) is a critical host factor for HIV transcription, yet pharmacological inhibition of its CDK9 subunit yields transient suppression with cytotoxicity. We identify that the integrator-PP2A complex enhances the potency and durability of CDK9 inhibition without added toxicity. Activation of PP2A with the small-molecule SMAP-2, combined with a low dose of the CDK9 inhibitor AZD4573, suppresses HIV transcription in CD4⁺ T cells, persisting for 7 days after drug withdrawal. Mechanistically, the drug combination increases integrator recruitment and repressive chromatin marks, decreases RNA polymerase II occupancy and C-terminal domain (CTD) phosphorylation at HIV promoter, and reduces short and long HIV transcripts, without global T cell activation, proliferation or broad transcriptome changes. The drug combination's HIV-inhibiting effect is somewhat resistant against elevated HIV activity in the presence of cocaine or morphine. These findings reveal cooperative P-TEFb inhibition and integrator activation as a promising strategy for durable HIV silencing.
SN - 2589-0042
ER -