1/25 – Roy Dar, University of Illinois at Urbana-Champaign
January 25, 2021
12:00 PM - 1:00 PM
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Title: Screening for Gene Expression Fluctuations Reveals Treatments that Control HIV Decision-Making
Abstract: Stochastic fluctuations are inherent to gene expression and can drive cell-fate specification. We previously used such fluctuations to modulate reactivation of HIV from latency—a quiescent state that is a major barrier to an HIV cure. High-throughput flow cytometry identified 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, whereas rare noise suppressors stabilized latency. Therapies that reactivate and clear the latent reservoir are only partially effective, while latency promoting agents (LPAs) used to suppress reactivation and stabilize latency are under-studied and lack diversity in their mechanisms of action. Recently we revealed additional LPAs using a high-throughput single-cell imaging drug screen for gene expression dynamics of a minimal HIV gene circuit. The LPAs reduced reactivation of latency in both Jurkat and primary cell models when challenged by synergistic and potent combinations of HIV activators. The discovered LPAs may provide new strategies to complement antiretroviral treatments. Screening for gene expression noise presents an unexplored and quantitative axis for drug discovery in other disease and diverse cell-fate decisions.
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