Leor Weinberger, PhD
Dr. Weinberger and colleagues pioneered the study of HIVâs decision circuit and demonstrated that stochastic ânoiseâ in gene expressionâBrownian fluctuations arising from diffusion-limited reactionsâcan drive fate-selection decisions. The labâs studies identified the molecular sources of noise in HIV, exposed the mechanisms regulating noise, and determined how feedback architectures tune noise for fate selection. The techniques developed for HIV also enabled the labâs discovery of the first transcriptional accelerator circuitâa high-cooperativity feedback motif that enables signaling systems (e.g. inflammatory responses) to overcome a fundamental tradeoff wherein increased speed generates higher/toxic amplitude. These accelerator circuits in herpesviruses are being exploited for a new class of antiviral target.
Collectively, the labâs studies overturned dogma that HIV latency was a deterministic cell-driven artifact and instead showed that HIV encodes a âhardwiredâ latency program that is evolutionarily optimized to harness noise. Gene-expression noise is now acknowledged as a major clinical barrier to reversing HIV latency and curing HIV. These studies laid the foundation for new therapeutic strategies targeting the HIV-latency circuit, including the labâs prediction and subsequent discovery of noise-enhancer molecules. Noise enhancers potentiate transcriptional activators, substantially increasing their efficacy and ability to activate persistent (i.e., latent) HIV.