Leor Weinberger, PhD

Senior Investigator, Gladstone Institute of Virology and Immunology
Professor
Department of Biochemistry and Biophysics
+1 415 734-4857

Dr. Weinberger and colleagues pioneered the study of HIV’s decision circuit and demonstrated that stochastic ‘noise’ in gene expression—Brownian fluctuations arising from diffusion-limited reactions—can drive fate-selection decisions. The lab’s 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 lab’s discovery of the first transcriptional accelerator circuit—a 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 lab’s studies overturned dogma that HIV latency was a deterministic cell-driven artifact and instead showed that HIV encodes a ‘hardwired’ 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 lab’s 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.

Primary Thematic Area: 
Virology & Microbial Pathogenesis
Secondary Thematic Area: 
Cancer Biology & Cell Signaling
Research Summary: 
Regulatory Circuitry of Viruses and Engineering Novel Therapeutics

Websites

Publications: 

Transcriptional Bursting Explains the Noise-Versus-Mean Relationship in mRNA and Protein Levels.

PloS one

Dar RD, Shaffer SM, Singh A, Razooky BS, Simpson ML, Raj A, Weinberger LS

The HIV-1 Tat Protein Is Monomethylated at Lysine 71 by the Lysine Methyltransferase KMT7.

The Journal of biological chemistry

Ali I, Ramage H, Boehm D, Dirk LM, Sakane N, Hanada K, Pagans S, Kaehlcke K, Aull K, Weinberger L, Trievel R, Schnoelzer M, Kamada M, Houtz R, Ott M

Conflicting Selection Pressures Will Constrain Viral Escape from Interfering Particles: Principles for Designing Resistance-Proof Antivirals.

PLoS computational biology

Rast LI, Rouzine IM, Rozhnova G, Bishop L, Weinberger AD, Weinberger LS

Exploiting Genetic Interference for Antiviral Therapy.

PLoS genetics

Tanner EJ, Kirkegaard KA, Weinberger LS

A minimal fate-selection switch.

Current opinion in cell biology

Weinberger LS