RT Journal Article
SR Electronic
T1 Gliotoxin, identified from a screen of fungal metabolites, disrupts 7SK snRNP, releases P-TEFb, and reverses HIV-1 latency
JF Science Advances
JO Sci Adv
FD American Association for the Advancement of Science
SP eaba6617
DO 10.1126/sciadv.aba6617
VO 6
IS 33
A1 Stoszko, Mateusz
A1 Al-Hatmi, Abdullah M. S.
A1 Skriba, Anton
A1 Roling, Michael
A1 Ne, Enrico
A1 Crespo, Raquel
A1 Mueller, Yvonne M.
A1 Najafzadeh, Mohammad Javad
A1 Kang, Joyce
A1 Ptackova, Renata
A1 LeMasters, Elizabeth
A1 Biswas, Pritha
A1 Bertoldi, Alessia
A1 Kan, Tsung Wai
A1 de Crignis, Elisa
A1 Sulc, Miroslav
A1 Lebbink, Joyce H.G.
A1 Rokx, Casper
A1 Verbon, Annelies
A1 van Ijcken, Wilfred
A1 Katsikis, Peter D.
A1 Palstra, Robert-Jan
A1 Havlicek, Vladimir
A1 de Hoog, Sybren
A1 Mahmoudi, Tokameh
YR 2020
UL http://advances.sciencemag.org/content/6/33/eaba6617.abstract
AB A leading pharmacological strategy toward 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 as a source of bioactive 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 positive transcription elongation factor b (P-TEFb) inhibitory 7SK small nuclear ribonucleoprotein (snRNP) complex, to be significantly reduced upon GTX treatment of CD4+ T cells. GTX directly disrupted 7SK snRNP by targeting La-related protein 7 (LARP7), releasing active P-TEFb, which phosphorylated RNA polymerase II (Pol II) C-terminal domain (CTD), inducing HIV transcription.