| Autor: |
Pritha Biswas, Mateusz Stoszko, Yvonne M. Mueller, Abdullah M. S. Al-Hatmi, Wilfred F. J. van IJcken, Alessia Bertoldi, Robert-Jan Palstra, Miroslav Sulc, Joyce H.G. Lebbink, Elisa De Crignis, Sybren de Hoog, Raquel Crespo, Enrico Ne, Joyce Kang, Renata Ptackova, Anton Škríba, Peter D. Katsikis, Mohammad Javad Najafzadeh, Tokameh Mahmoudi, Annelies Verbon, Tsung Wai Kan, Vladimír Havlíček, Casper Rokx, Michael Roling |
| Rok vydání: |
2019 |
| Předmět: |
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| Popis: |
A leading pharmacological strategy towards HIV cure requires “shock” or activation of HIV gene expression in latently infected cells with Latency Reversal Agents (LRAs) followed by their subsequent clearance. In a screen for novel LRAs we used fungal secondary metabolites (extrolites) as a source of bio-active molecules. Using orthogonal mass spectrometry (MS) coupled to latency reversal bioassays, we identified gliotoxin (GTX) as a novel LRA. GTX significantly induced HIV-1 gene expression in latent ex vivo infected primary cells and in CD4+ T cells from all aviremic HIV-1+ participants. RNA sequencing identified 7SK RNA, the scaffold of the P-TEFb inhibitory 7SK snRNP complex to be significantly reduced upon GTX treatment of independent donor CD4+T cells. GTX disrupted 7SK snRNP, releasing active P-TEFb, which then phosphorylated RNA Pol II CTD, inducing HIV transcription. Our data highlight the power of combining a medium throughput bioassay, mycology and orthogonal mass spectrometry to identify novel potentially therapeutic compounds. |
| Databáze: |
OpenAIRE |
| Externí odkaz: |
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