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Screening for noise in gene expression identifies drug synergies

Science  20 Jun 2014:
Vol. 344, Issue 6190, pp. 1392-1396
DOI: 10.1126/science.1250220

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Noisy genes flush HIV out of hiding

HIV can hide in the body, making it hard to kill with drugs. Increasing variation or “noise” in the virus's gene expression turns out to be an effective strategy for reactivating latent HIV. Once reawakened, the virus is more sensitive to antiviral drugs. Dar et al. screened for agents that increased variation in the expression of HIV genes. In a model system with HIV-infected human cells, the noise enhancers worked with existing compounds used to reactivate latent HIV and helped eradicate the virus.

Science, this issue p. 1392

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.

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