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Gliotoxin, identified from a screen of Aspergillus fumigatus metabolites, reverses HIV-1 latency via release of P-TEFb

ABSTRACT: A leading pharmacological strategy towards HIV cure requires “shock” or activation of expression of the HIV genome in latently infected cells with Latency Reversal Agents (LRAs) followed by their subsequent clearance. As a source of bio-active molecules we used fungal secondary metabolites (extrolites) in a screen for novel LRAs. We used orthogonal mass spectrometry (MS) coupled to latency reversal bioassays, and identified gliotoxin (GTX) to potently reverse latency. 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 to be most significantly downregulated in independent donors upon GTX treatment of CD4+ T cells. GTX disrupted the 7SK snRNP complex causing release of P-TEFb, which induced phosphorylation of RNA Pol II CTD, and increased HIV transcription. Our data highlight the power of combining low throughput bioassays, mycology and orthogonal mass spectrometry as an approach to screen for and characterize novel LRAs.

ORGANISM(S): Homo sapiens

PROVIDER: GSE135184 | GEO | 2020/08/31

REPOSITORIES: GEO

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A CRISPR screen of HIV dependency factors reveals CCNT1 is non-essential in T cells but required for HIV-1 reactivation from latency [CRISPR]

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