Journal
SCIENCE
Volume 344, Issue 6190, Pages 1392-1396Publisher
AMER ASSOC ADVANCEMENT SCIENCE
DOI: 10.1126/science.1250220
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Funding
- NIH National Research Service Award fellowship [AI104380]
- NIH Director's New Innovator Award [DP2-OD006677]
- NIH Delaney Collaboratory of AIDS Researchers for a Cure [U19AI096113]
- UCSF CTSI-SOS Award
- UCSF-GIVI CFAR [P30AI027763]
- UCSF-CSSB [P50GM081879]
- Pew Scholars in the Biomedical Sciences
- Alfred P. Sloan Foundation
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Stochastic fluctuations are inherent to gene expression and can drive cell-fate specification. We used such fluctuations to modulate reactivation of HIV from latency-a quiescent state that is a major barrier to an HIV cure. By screening a diverse library of bioactive small molecules, we identified more than 80 compounds that modulated HIV gene-expression fluctuations (i.e., noise), without changing mean expression. These noise-modulating compounds would be neglected in conventional screens, and yet, they synergized with conventional transcriptional activators. Noise enhancers reactivated latent cells significantly better than existing best-in-class reactivation drug combinations (and with reduced off-target cytotoxicity), whereas noise suppressors stabilized latency. Noise-modulating chemicals may provide novel probes for the physiological consequences of noise and an unexplored axis for drug discovery, allowing enhanced control over diverse cell-fate decisions.
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