Work

“Locking” CDK9 inhibition by activating integrator function in HIV transcription

Year: 2026

Type: article

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.

Source: iScience

DOI: 10.1016/j.isci.2026.117894

Authors: Zichong Li, Francisco J. Zapatero-Belinchón, Patrik Geleziunas, Melanie Ott

Institutions: Gladstone Institutes, University of Toronto, University of California, San Francisco, Chan Zuckerberg Biohub San Francisco

Language: English

Topic: HIV Research and Treatment

Subfield: Virology

Field: Immunology and Microbiology

Domain: Life Sciences

SDG: Good health and well-being

Open Access status: gold

Estimated APC paid: $3,240