Leor Weinberger

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(415) 734-4857

1650 Owens St
San Francisco, CA 94107

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  • Professor, UCSF School of Medicine

Biography

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.

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  1. Dar RD, Shaffer SM, Singh A, Razooky BS, Simpson ML, Raj A, Weinberger LS. Transcriptional Bursting Explains the Noise-Versus-Mean Relationship in mRNA and Protein Levels. PLoS One. 2016; 11(7):e0158298. View on Pubmed
  2. 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. The HIV-1 Tat Protein Is Monomethylated at Lysine 71 by the Lysine Methyltransferase KMT7. J Biol Chem. 2016 Jul 29; 291(31):16240-8. View on Pubmed
  3. Rast LI, Rouzine IM, Rozhnova G, Bishop L, Weinberger AD, Weinberger LS. Conflicting Selection Pressures Will Constrain Viral Escape from Interfering Particles: Principles for Designing Resistance-Proof Antivirals. PLoS Comput Biol. 2016 May; 12(5):e1004799. View on Pubmed
  4. Tanner EJ, Kirkegaard KA, Weinberger LS. Exploiting Genetic Interference for Antiviral Therapy. PLoS Genet. 2016 May; 12(5):e1005986. View on Pubmed
  5. Weinberger LS. A minimal fate-selection switch. Curr Opin Cell Biol. 2015 Dec; 37:111-8. View on Pubmed
  6. Dar RD, Razooky BS, Weinberger LS, Cox CD, Simpson ML. The Low Noise Limit in Gene Expression. PLoS One. 2015; 10(10):e0140969. View on Pubmed
  7. Rouzine IM, Weinberger AD, Weinberger LS. An evolutionary role for HIV latency in enhancing viral transmission. Cell. 2015 Feb 26; 160(5):1002-12. View on Pubmed
  8. Razooky BS, Pai A, Aull K, Rouzine IM, Weinberger LS. A hardwired HIV latency program. Cell. 2015 Feb 26; 160(5):990-1001. View on Pubmed
  9. Jung SY, Notton T, Fong E, Shusteff M, Weinberger LS. Spatial tuning of acoustofluidic pressure nodes by altering net sonic velocity enables high-throughput, efficient cell sorting. Lab Chip. 2015 Feb 21; 15(4):1000-3. View on Pubmed
  10. Rouzine IM, Razooky BS, Weinberger LS. Stochastic variability in HIV affects viral eradication. Proc Natl Acad Sci U S A. 2014 Sep 16; 111(37):13251-2. View on Pubmed
  11. Notton T, Sardanyés J, Weinberger AD, Weinberger LS. The case for transmissible antivirals to control population-wide infectious disease. Trends Biotechnol. 2014 Aug; 32(8):400-5. View on Pubmed
  12. Dar RD, Hosmane NN, Arkin MR, Siliciano RF, Weinberger LS. Screening for noise in gene expression identifies drug synergies. Science. 2014 Jun 20; 344(6190):1392-6. View on Pubmed
  13. Rouzine IM, Coffin JM, Weinberger LS. Fifteen years later: hard and soft selection sweeps confirm a large population number for HIV in vivo. PLoS Genet. 2014 Feb; 10(2):e1004179. View on Pubmed
  14. Fong EJ, Johnston AC, Notton T, Jung SY, Rose KA, Weinberger LS, Shusteff M. Acoustic focusing with engineered node locations for high-performance microfluidic particle separation. Analyst. 2014 Mar 7; 139(5):1192-200. View on Pubmed
  15. Weinberger AD, Weinberger LS. Stochastic fate selection in HIV-infected patients. Cell. 2013 Oct 24; 155(3):497-9. View on Pubmed
  16. Rouzine IM, Weinberger LS. Reply to "Coadaptive stability of interfering particles with HIV-1 when there is an evolutionary conflict". J Virol. 2013 Sep; 87(17):9960-2. View on Pubmed
  17. Gardner TJ, Bolovan-Fritts C, Teng MW, Redmann V, Kraus TA, Sperling R, Moran T, Britt W, Weinberger LS, Tortorella D. Development of a high-throughput assay to measure the neutralization capability of anti-cytomegalovirus antibodies. Clin Vaccine Immunol. 2013 Apr; 20(4):540-50. View on Pubmed
  18. Teng MW, Bolovan-Fritts C, Dar RD, Womack A, Simpson ML, Shenk T, Weinberger LS. An endogenous accelerator for viral gene expression confers a fitness advantage. Cell. 2012 Dec 21; 151(7):1569-80. View on Pubmed
  19. Rouzine IM, Weinberger LS. Design requirements for interfering particles to maintain coadaptive stability with HIV-1. J Virol. 2013 Feb; 87(4):2081-93. View on Pubmed
  20. Razooky BS, Gutierrez E, Terry VH, Spina CA, Groisman A, Weinberger LS. Microwell devices with finger-like channels for long-term imaging of HIV-1 expression kinetics in primary human lymphocytes. Lab Chip. 2012 Nov 7; 12(21):4305-12. View on Pubmed
  21. Dar RD, Razooky BS, Singh A, Trimeloni TV, McCollum JM, Cox CD, Simpson ML, Weinberger LS. Transcriptional burst frequency and burst size are equally modulated across the human genome. Proc Natl Acad Sci U S A. 2012 Oct 23; 109(43):17454-9. View on Pubmed
  22. Boehm D, Calvanese V, Dar RD, Xing S, Schroeder S, Martins L, Aull K, Li PC, Planelles V, Bradner JE, Zhou MM, Siliciano RF, Weinberger L, Verdin E, Ott M. BET bromodomain-targeting compounds reactivate HIV from latency via a Tat-independent mechanism. Cell Cycle. 2013 Feb 1; 12(3):452-62. View on Pubmed
  23. Singh A, Razooky BS, Dar RD, Weinberger LS. Dynamics of protein noise can distinguish between alternate sources of gene-expression variability. Mol Syst Biol. 2012; 8:607. View on Pubmed
  24. Metzger VT, Lloyd-Smith JO, Weinberger LS. Autonomous targeting of infectious superspreaders using engineered transmissible therapies. PLoS Comput Biol. 2011 Mar; 7(3):e1002015. View on Pubmed
  25. Franz K, Singh A, Weinberger LS. Lentiviral vectors to study stochastic noise in gene expression. Methods Enzymol. 2011; 497:603-22. View on Pubmed
  26. Razooky BS, Weinberger LS. Mapping the architecture of the HIV-1 Tat circuit: A decision-making circuit that lacks bistability and exploits stochastic noise. Methods. 2011 Jan; 53(1):68-77. View on Pubmed
  27. Singh A, Razooky B, Cox CD, Simpson ML, Weinberger LS. Transcriptional bursting from the HIV-1 promoter is a significant source of stochastic noise in HIV-1 gene expression. Biophys J. 2010 Apr 21; 98(8):L32-4. View on Pubmed
  28. Weinberger AD, Perelson AS, Ribeiro RM, Weinberger LS. Accelerated immunodeficiency by anti-CCR5 treatment in HIV infection. PLoS Comput Biol. 2009 Aug; 5(8):e1000467. View on Pubmed
  29. Singh A, Weinberger LS. Stochastic gene expression as a molecular switch for viral latency. Curr Opin Microbiol. 2009 Aug; 12(4):460-6. View on Pubmed
  30. Weinberger LS, Dar RD, Simpson ML. Transient-mediated fate determination in a transcriptional circuit of HIV. Nat Genet. 2008 Apr; 40(4):466-70. View on Pubmed
  31. Weinberger LS, Shenk T. An HIV feedback resistor: auto-regulatory circuit deactivator and noise buffer. PLoS Biol. 2007 Jan; 5(1):e9. View on Pubmed
  32. Weinberger LS, Burnett JC, Toettcher JE, Arkin AP, Schaffer DV. Stochastic gene expression in a lentiviral positive-feedback loop: HIV-1 Tat fluctuations drive phenotypic diversity. Cell. 2005 Jul 29; 122(2):169-82. View on Pubmed
  33. Weinberger LS, Schaffer DV, Arkin AP. Theoretical design of a gene therapy to prevent AIDS but not human immunodeficiency virus type 1 infection. J Virol. 2003 Sep; 77(18):10028-36. View on Pubmed
  34. Rosen HR, Ribeiro RR, Weinberger L, Wolf S, Chung M, Gretch DR, Perelson AS. Early hepatitis C viral kinetics correlate with long-term outcome in patients receiving high dose induction followed by combination interferon and ribavirin therapy. J Hepatol. 2002 Jul; 37(1):124-30. View on Pubmed
  35. Mohri H, Perelson AS, Tung K, Ribeiro RM, Ramratnam B, Markowitz M, Kost R, Hurley A, Weinberger L, Cesar D, Hellerstein MK, Ho DD. Increased turnover of T lymphocytes in HIV-1 infection and its reduction by antiretroviral therapy. J Exp Med. 2001 Nov 5; 194(9):1277-87. View on Pubmed
  36. Shiratori Y, Perelson AS, Weinberger L, Imazeki F, Yokosuka O, Nakata R, Ihori M, Hirota K, Ono N, Kuroda H, Motojima T, Nishigaki M, Omata M. Different turnover rate of hepatitis C virus clearance by different treatment regimen using interferon-beta. J Hepatol. 2000 Aug; 33(2):313-22. View on Pubmed
  37. Jin X, Bauer DE, Tuttleton SE, Lewin S, Gettie A, Blanchard J, Irwin CE, Safrit JT, Mittler J, Weinberger L, Kostrikis LG, Zhang L, Perelson AS, Ho DD. Dramatic rise in plasma viremia after CD8(+) T cell depletion in simian immunodeficiency virus-infected macaques. J Exp Med. 1999 Mar 15; 189(6):991-8. View on Pubmed