William and Ute Bowes Distinguished Professor; Director, Gladstone Centre for Cell Circuitry
[Host: Prof Valerie Mizrahi]
Professor Weinberger’s group pioneered the study of the HIV Tat transcriptional circuit (Weinberger* et al. Cell 2005), which provided the first experimental evidence that stochastic fluctuations (‘noise’) in transcription are harnessed for biological fate decisions. They went on to identify the molecular sources of noise in HIV transcription, expose the transcriptional mechanisms regulating noise, and determine how Tat feedback tunes noise for HIV fate selection. The quantitative techniques developed enabled their discovery of the transcriptional accelerator circuit (Teng et al. Cell 2012), a high-cooperativity feedback motif currently being exploited as a new class of antiviral drug target (patent #WO2014127148, under license for further development).
Collectively, their studies overturned dogma that viral latency was a deterministic cell-driven ‘epiphenomenon’ and instead showed that latency is a ‘hardwired’ viral transcriptional program that is evolutionarily optimized to harness transcriptional fluctuations (Razooky et al. Cell 2015; Rouzine et al. Cell 2015). Transcriptional noise has since gained recognition as a clinical barrier to reversing HIV latency and curing HIV (Weinberger &Weinberger, Cell 2013). These studies laid the foundation for their prediction and subsequent discovery of transcriptional noise-enhancer molecules (Dar et al. Science 2014) and noise-suppressor molecules (Hansen et al Cell 2018).