Science 344, 1392–1396 (2014)

Credit: SCIENCE

The ability of HIV-1 to remain in a proviral latent state for extended periods, escaping antiviral drug action, necessitates lifelong therapy for infected individuals. Reactivation of latent virus to an actively replicating state in combination with traditional antivirals has been proposed as an eradication strategy. Small molecules exist that promote HIV reactivation, but these have all failed to fully reactivate latent virus. Dar et al. sought to capitalize on transcriptional noise—the stochastic nature of gene expression that can generate high variability in HIV gene products—to identify new compounds that can reactivate latent HIV. They proposed that compounds that could increase stochastic fluctuations in transcription from the HIV long terminal repeat (LTR) promoter would synergize with known transcriptional activators such as TNF that increase the mean expression level, to enhance HIV reactivation. The authors performed a small-molecule screen on a T-cell line containing GFP under the control of the LTR promoter with a library of 1,600 FDA-approved compounds and found 100 compounds that enhance GFP expression noise. Using this GFP system, the authors further showed that known chromatin modifiers that affect latency acted as noise enhancers, supporting their model that synergistic combinations of noise enhancers and activators can reactivate latent HIV. Among the new noise-enhancing compounds, >70% synergized with TNF to enhance reactivation. 'Noise screening' represents a new avenue to defining synergistic drug combinations in any system where fate choices are made in response to stochastic gene expression.