What is it about?

Spontaneous reactivation of latent HIV into active replication remains a primary barrier to achieving a cure. We utilized time-lapse fluorescence microscopy to screen for modulators of viral gene expression fluctuations that would be overlooked by measuring shifts in mean gene expression levels alone. Our screen targeted the noise in gene expression by imaging a cell line containing a fluorescent reporter of a minimal HIV feedback circuit with ~1,800 drug perturbations. Further testing of 115 noise modulators yielded 3 latency promoting agents (LPAs), and researching their functional analogues yielded 2 additional LPAs. In total we discovered 5 LPAs capable of suppressing reactivation of cells latently infected with HIV.

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Why is it important?

The time-series drug screen is a novel experimental approach to detect noise modulators of a viral gene circuit and may be extended to bias decisions in other noise-driven systems or diseases. The detected LPAs would be overlooked by screening for changes in mean gene expression alone. The 5 LPAs discovered will expand the palette of currently existing LPAs available to the HIV cure research community and potentially lead to novel mechanisms for “blocking and locking” latency. 1 of the 5 LPAs discovered is FDA approved and holds promise in its safety and availability.

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This page is a summary of: Screening for gene expression fluctuations reveals latency-promoting agents of HIV, Proceedings of the National Academy of Sciences, March 2021, Proceedings of the National Academy of Sciences, DOI: 10.1073/pnas.2012191118.
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