Abstract
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.
