Leor Weinberger’s lab studies fundamental processes of viral biology to develop innovative first-in-class therapies against HIV. The lab discovered a viral program that allows HIV to grow in some cells and remain dormant in others, and a new class of molecules that manipulate this program in infected individuals. The group developed and pioneered the concept of Therapeutic Interfering Particles (TIPs), single-administration, resistance-proof therapeutics that could treat HIV in resource-limited settings, such as sub-Saharan Africa and in injection drug users. The group also develops novel therapies for SAR-CoV-2, herpes simplex, and cytomegalovirus, the leading cause of birth defects and transplant failures.
Areas of Expertise
Weinberger and his team are known for discovering HIV’s latency “circuit”. HIV latency is a viral dormant state and the chief barrier to an HIV cure. Weinberger’s lab characterized the molecular mechanisms regulating HIV stochastic fluctuations (“noise”) and overturned dogma to show that HIV evolved circuitry to control latency by manipulating noise. These studies led to the lab’s discovery of a new class of molecules (noise enhancers), and of gene circuits in herpesviruses that are being exploited as a new class of antiviral targets.
The lab couples computational and experimental approaches, including quantitative, single-cell and single-molecule microscopy and mathematical modeling. An exciting illustration is the team’s recent effort to engineer resistance-proof, single-administration therapies for HIV. These therapies would benefit the highest-risk populations who most need therapy, and are aimed specifically at resource-poor settings, such as sub-Saharan Africa or at people who inject drugs.
Senior Investigator, Gladstone Institutes
Director, Center for Cell Circuitry, Gladstone Institutes
William and Ute Bowes Distinguished Professor
Professor of Pharmaceutical Chemistry, Biochemistry, and Biophysics, UC San Francisco
Leor S. Weinberger, PhD, is the director of the Center for Cell Circuitry and a senior investigator at Gladstone Institutes. He is also the William and Ute Bowes Distinguished Professor, as well as a professor of chemistry, biochemistry, and biophysics, at UC San Francisco.
Weinberger earned a BS in biology and physics from the University of Maryland, College Park, and a PhD in biophysics from UC Berkeley, where he was a Howard Hughes Medical Institute Predoctoral Fellow. He received postdoctoral training at Princeton University as a Lewis Thomas Fellow, working with Thomas Shenk and David Botstein. Before joining Gladstone, Weinberger was an assistant professor of chemistry and biochemistry at UC San Diego.
Weinberger has been named an Alfred P. Sloan Foundation Research Fellow and won several awards, including the W.M. Keck Foundation Research Excellence Award, the California HIV/AIDS Young Investigator Innovative Development Award, and the Bill and Melinda Gates Grand Challenges Award. He is also the only individual ever to win the NIH Director’s Pioneer, Avant-Garde, and New Innovator awards. Weinberger is a member of numerous scientific societies and serves on the Innovation Review Panel for the Bill and Melinda Gates Foundation.
How Did You Get Your Start in Science?
“I had several extremely dedicated undergraduate mentors who encouraged me to combine my math and physics interests with biology and gave me a place in their labs.”
Honors and Awards
2019 Keynote Speaker, Computational and Genomic Biology Retreat, UC Berkeley
2018 The Windsor Cutting Memorial Lectureship, Stanford University
2017 The Svedberg Lecture, Uppsala University and Karolinska Institut, Sweden
2017 Keynote Speaker, Whitehead Fellows Seminar Forum, Whitehead Institute, Cambridge, MA
2016 Butler Seminar, Department of Molecular Biology, Princeton University
2016 J.W. Kieckhefer Distinguished Speaker, MIT
2016 Blavatnik Scholar
2015 Elected Fellow, American Institute of Medical and Biomedical Engineers
2013 Pioneer Award, National Institutes of Health
2011 Alfred P. Sloan Foundation Research Fellow
2009 NIH Director’s New Innovator Award
2009 W.M. Keck Foundation Research Excellence Award
2009 Bill and Melinda Gates Foundation, Grand Challenges Explorations Award
2009 California HIV/AIDS Young Investigator Innovative Development Award
2008 Pew Scholar in the Biomedical Sciences
2008 NIH K25 Career Development Award
2006 External Thesis Reviewer, Department of Applied Maths, Witz University, South Africa
2006 Princeton University Early Promotion (Research Associate to Research Staff)
2006 Best Postdoctoral Research Award, Department of Biology, Princeton University
2006 Lewis Thomas Fellowship, Princeton University
2003 Berkeley Microscopy Award, UC Berkeley
1999 Howard Hughes Medical Institute Predoctoral Fellowship
1999 Chancellor’s Fellowship, UC Berkeley
1999 Eugene Cota Robles Fellowship, UC Berkeley
1998 DOE (URS) Research Scholarship, Los Alamos National Lab
1998 Kupcinet International Science Research Scholarship, Weizmann Institute of Science, Israel
1997 HHMI Undergraduate Research Fellowship, 2nd award
1997 NSF (REU) Research Scholarship, UC San Diego
1996 Howard Hughes Medical Institute Undergraduate Research Scholar, University of Maryland
1996 Maryland Distinguished Scholar
1996 University Honors Research Grant, University of Maryland
1996 John Prost Scholarly Writing Award, University of Maryland, Honors Program
1993 FAES Fellow, National Institutes of Health
- Disrupting autorepression circuitry generates "open-loop lethality" to yield escape-resistant antiviral agents. Chaturvedi S, Pablo M, Wolf M, Rosas-Rivera D, Calia G, Kumar AJ, Vardi N, Du K, Glazier J, Ke R, Chan MF, Perelson AS, Weinberger LS. Cell. 2022 06 09; 185(12):2086-2102.e22.
- A DNA repair pathway can regulate transcriptional noise to promote cell fate transitions. Leor S. Weinberger. Biophysical Journal. 2022 Feb 1; 121(3):447a.
- Brahma safeguards canalization of cardiac mesoderm differentiation. Hota SK, Rao KS, Blair AP, Khalilimeybodi A, Hu KM, Thomas R, So K, Kameswaran V, Xu J, Polacco BJ, Desai RV, Chatterjee N, Hsu A, Muncie JM, Blotnick AM, Winchester SAB, Weinberger LS, Hüttenhain R, Kathiriya IS, Krogan NJ, Saucerman JJ, Bruneau BG. Nature. 2022 02; 602(7895):129-134.
- Identification of a therapeutic interfering particle-A single-dose SARS-CoV-2 antiviral intervention with a high barrier to resistance. Chaturvedi S, Vasen G, Pablo M, Chen X, Beutler N, Kumar A, Tanner E, Illouz S, Rahgoshay D, Burnett J, Holguin L, Chen PY, Ndjamen B, Ott M, Rodick R, Rogers T, Smith DM, Weinberger LS. Cell. 2021 12 09; 184(25):6022-6036.e18.
- A DNA repair pathway can regulate transcriptional noise to promote cell fate transitions. Desai RV, Chen X, Martin B, Chaturvedi S, Hwang DW, Li W, Yu C, Ding S, Thomson M, Singer RH, Coleman RA, Hansen MMK, Weinberger LS. Science. 2021 08 20; 373(6557).
- Evaluation of Singer et al.: Technical points on analyzing viral replication kinetics in single cells. Chen X, Pablo M, Weinberger L. Cell Syst. 2021 03 17; 12(3):205-206.
- RanDeL-Seq: a High-Throughput Method to Map Viral cis- and trans-Acting Elements. Notton T, Glazier JJ, Saykally VR, Thompson CE, Weinberger LS. mBio. 2021 01 19; 12(1).
- A molecular mechanism for probabilistic bet hedging and its role in viral latency. Chaturvedi S, Klein J, Vardi N, Bolovan-Fritts C, Wolf M, Du K, Mlera L, Calvert M, Moorman NJ, Goodrum F, Huang B, Weinberger LS. Proc Natl Acad Sci U S A. 2020 07 21; 117(29):17240-17248.
- The HSV-1 ICP4 Transcriptional Auto-Repression Circuit Functions as a Transcriptional "Accelerator" Circuit. Chaturvedi S, Engel R, Weinberger L. Front Cell Infect Microbiol. 2020; 10:265.
- Noise-driven cellular heterogeneity in circadian periodicity. Li Y, Shan Y, Desai RV, Cox KH, Weinberger LS, Takahashi JS. Proc Natl Acad Sci U S A. 2020 05 12; 117(19):10350-10356.
- HIV Latency: Stochastic across Multiple Scales. Hansen MMK, Martin B, Weinberger LS. Cell Host Microbe. 2019 12 11; 26(6):703-705.
- Attacking Latent HIV with convertibleCAR-T Cells, a Highly Adaptable Killing Platform. Herzig E, Kim KC, Packard TA, Vardi N, Schwarzer R, Gramatica A, Deeks SG, Williams SR, Landgraf K, Killeen N, Martin DW, Weinberger LS, Greene WC. Cell. 2019 10 31; 179(4):880-894.e10.
- Post-Transcriptional Noise Control. Hansen MMK, Weinberger LS. Bioessays. 2019 07; 41(7):e1900044.
- Cytoplasmic Amplification of Transcriptional Noise Generates Substantial Cell-to-Cell Variability. Hansen MMK, Desai RV, Simpson ML, Weinberger LS. Cell Syst. 2018 10 24; 7(4):384-397.e6.
- Feedback-mediated signal conversion promotes viral fitness. Vardi N, Chaturvedi S, Weinberger LS. Proc Natl Acad Sci U S A. 2018 09 11; 115(37):E8803-E8810.
- A Post-Transcriptional Feedback Mechanism for Noise Suppression and Fate Stabilization. Hansen MMK, Wen WY, Ingerman E, Razooky BS, Thompson CE, Dar RD, Chin CW, Simpson ML, Weinberger LS. Cell. 2018 06 14; 173(7):1609-1621.e15.
- A Bioreactor Method to Generate High-titer, Genetically Stable, Clinical-isolate Human Cytomegalovirus. Saykally VR, Rast LI, Sasaki J, Jung SY, Bolovan-Fritts C, Weinberger LS. Bio Protoc. 2017 Nov 05; 7(21).
- Nonlatching positive feedback enables robust bimodality by decoupling expression noise from the mean. Razooky BS, Cao Y, Hansen MMK, Perelson AS, Simpson ML, Weinberger LS. PLoS Biol. 2017 Oct; 15(10):e2000841.
- Fate-Regulating Circuits in Viruses: From Discovery to New Therapy Targets. Pai A, Weinberger LS. Annu Rev Virol. 2017 09 29; 4(1):469-490.
- Transient Thresholding: A Mechanism Enabling Noncooperative Transcriptional Circuitry to Form a Switch. Aull KH, Tanner EJ, Thomson M, Weinberger LS. Biophys J. 2017 Jun 06; 112(11):2428-2438.
- Transcriptional Bursting Explains the Noise-Versus-Mean Relationship in mRNA and Protein Levels. Dar RD, Shaffer SM, Singh A, Razooky BS, Simpson ML, Raj A, Weinberger LS. PLoS One. 2016; 11(7):e0158298.
- The HIV-1 Tat Protein Is Monomethylated at Lysine 71 by the Lysine Methyltransferase KMT7. 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. J Biol Chem. 2016 07 29; 291(31):16240-8.
- Conflicting Selection Pressures Will Constrain Viral Escape from Interfering Particles: Principles for Designing Resistance-Proof Antivirals. Rast LI, Rouzine IM, Rozhnova G, Bishop L, Weinberger AD, Weinberger LS. PLoS Comput Biol. 2016 05; 12(5):e1004799.
- Exploiting Genetic Interference for Antiviral Therapy. Tanner EJ, Kirkegaard KA, Weinberger LS. PLoS Genet. 2016 05; 12(5):e1005986.
- A minimal fate-selection switch. Weinberger LS. Curr Opin Cell Biol. 2015 Dec; 37:111-8.
- The Low Noise Limit in Gene Expression. Dar RD, Razooky BS, Weinberger LS, Cox CD, Simpson ML. PLoS One. 2015; 10(10):e0140969.
- A hardwired HIV latency program. Razooky BS, Pai A, Aull K, Rouzine IM, Weinberger LS. Cell. 2015 Feb 26; 160(5):990-1001.
- An evolutionary role for HIV latency in enhancing viral transmission. Rouzine IM, Weinberger AD, Weinberger LS. Cell. 2015 Feb 26; 160(5):1002-1012.
- Spatial tuning of acoustofluidic pressure nodes by altering net sonic velocity enables high-throughput, efficient cell sorting. Jung SY, Notton T, Fong E, Shusteff M, Weinberger LS. Lab Chip. 2015 Feb 21; 15(4):1000-3.
- Stochastic variability in HIV affects viral eradication. Rouzine IM, Razooky BS, Weinberger LS. Proc Natl Acad Sci U S A. 2014 Sep 16; 111(37):13251-2.
- The case for transmissible antivirals to control population-wide infectious disease. Notton T, Sardanyés J, Weinberger AD, Weinberger LS. Trends Biotechnol. 2014 Aug; 32(8):400-5.
- Screening for noise in gene expression identifies drug synergies. Dar RD, Hosmane NN, Arkin MR, Siliciano RF, Weinberger LS. Science. 2014 Jun 20; 344(6190):1392-6.
- Fifteen years later: hard and soft selection sweeps confirm a large population number for HIV in vivo. Rouzine IM, Coffin JM, Weinberger LS. PLoS Genet. 2014 Feb; 10(2):e1004179.
- Acoustic focusing with engineered node locations for high-performance microfluidic particle separation. Fong EJ, Johnston AC, Notton T, Jung SY, Rose KA, Weinberger LS, Shusteff M. Analyst. 2014 Mar 07; 139(5):1192-200.
- Altering Stochastic Noise in Gene Expression for HIV Therapy. Roy D. Dar, Leor S. Weinberger. Biophysical Journal. 2014 Jan 1; 106(2):374a.
- Structure and Function of a Transcriptional ‘Accelerator’ Circuit. Roy Dar, Cynthia Bolovan-Fritts, Melissa Teng, Brian Linhares, Michael Simpson, Leor S. Weinberger. Biophysical Journal. 2014 Jan 1; 106(2):375a.
- Stochastic fate selection in HIV-infected patients. Weinberger AD, Weinberger LS. Cell. 2013 Oct 24; 155(3):497-9.
- Reply to "Coadaptive stability of interfering particles with HIV-1 when there is an evolutionary conflict". Rouzine IM, Weinberger LS. J Virol. 2013 Sep; 87(17):9960-2.
- Development of a high-throughput assay to measure the neutralization capability of anti-cytomegalovirus antibodies. Gardner TJ, Bolovan-Fritts C, Teng MW, Redmann V, Kraus TA, Sperling R, Moran T, Britt W, Weinberger LS, Tortorella D. Clin Vaccine Immunol. 2013 Apr; 20(4):540-50.
- An Endogenous Accelerator for Viral Gene Expression Confers a Fitness Advantage. Melissa W. Teng, Cynthia Bolovan-Fritts, Roy D. Dar, Andrew Womack, Michael L. Simpson, Thomas Shenk, Leor S. Weinberger. Cell. 2013 Feb 1; 152(5):1195.
- The quantitative theory of within-host viral evolution. Igor M Rouzine, Leor S Weinberger. Journal of Statistical Mechanics Theory and Experiment. 2013 Jan 16; 2013(01):p01009.
- An endogenous accelerator for viral gene expression confers a fitness advantage. Teng MW, Bolovan-Fritts C, Dar RD, Womack A, Simpson ML, Shenk T, Weinberger LS. Cell. 2012 Dec 21; 151(7):1569-80.
- Design requirements for interfering particles to maintain coadaptive stability with HIV-1. Rouzine IM, Weinberger LS. J Virol. 2013 Feb; 87(4):2081-93.
- Microwell devices with finger-like channels for long-term imaging of HIV-1 expression kinetics in primary human lymphocytes. Razooky BS, Gutierrez E, Terry VH, Spina CA, Groisman A, Weinberger LS. Lab Chip. 2012 Nov 07; 12(21):4305-12.
- Transcriptional burst frequency and burst size are equally modulated across the human genome. Dar RD, Razooky BS, Singh A, Trimeloni TV, McCollum JM, Cox CD, Simpson ML, Weinberger LS. Proc Natl Acad Sci U S A. 2012 Oct 23; 109(43):17454-9.
- BET bromodomain-targeting compounds reactivate HIV from latency via a Tat-independent mechanism. 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. Cell Cycle. 2013 Feb 01; 12(3):452-62.
- Dynamics of protein noise can distinguish between alternate sources of gene-expression variability. Singh A, Razooky BS, Dar RD, Weinberger LS. Mol Syst Biol. 2012; 8:607.
- Autonomous targeting of infectious superspreaders using engineered transmissible therapies. Metzger VT, Lloyd-Smith JO, Weinberger LS. PLoS Comput Biol. 2011 Mar; 7(3):e1002015.
- Lentiviral vectors to study stochastic noise in gene expression. Franz K, Singh A, Weinberger LS. Methods Enzymol. 2011; 497:603-22.
- Mapping the architecture of the HIV-1 Tat circuit: A decision-making circuit that lacks bistability and exploits stochastic noise. Razooky BS, Weinberger LS. Methods. 2011 Jan; 53(1):68-77.
- Transcriptional bursting from the HIV-1 promoter is a significant source of stochastic noise in HIV-1 gene expression. Singh A, Razooky B, Cox CD, Simpson ML, Weinberger LS. Biophys J. 2010 Apr 21; 98(8):L32-4.
- Accelerated immunodeficiency by anti-CCR5 treatment in HIV infection. Weinberger AD, Perelson AS, Ribeiro RM, Weinberger LS. PLoS Comput Biol. 2009 Aug; 5(8):e1000467.
- Stochastic gene expression as a molecular switch for viral latency. Singh A, Weinberger LS. Curr Opin Microbiol. 2009 Aug; 12(4):460-6.
- Negative Feedback Speeds Transcriptional Response-Time In Human Cytomegalovirus. Melissa L. Wong, Cynthia Bolovan-Fritts, Leor S. Weinberger. Biophysical Journal. 2009 Feb 1; 96(3):305a.
- Transient-mediated fate determination in a transcriptional circuit of HIV. Weinberger LS, Dar RD, Simpson ML. Nat Genet. 2008 Apr; 40(4):466-70.
- An HIV feedback resistor: auto-regulatory circuit deactivator and noise buffer. Weinberger LS, Shenk T. PLoS Biol. 2007 Jan; 5(1):e9.
- Stochastic gene expression in a lentiviral positive-feedback loop: HIV-1 Tat fluctuations drive phenotypic diversity. Weinberger LS, Burnett JC, Toettcher JE, Arkin AP, Schaffer DV. Cell. 2005 Jul 29; 122(2):169-82.
- Theoretical design of a gene therapy to prevent AIDS but not human immunodeficiency virus type 1 infection. Weinberger LS, Schaffer DV, Arkin AP. J Virol. 2003 Sep; 77(18):10028-36.
- Early hepatitis C viral kinetics correlate with long-term outcome in patients receiving high dose induction followed by combination interferon and ribavirin therapy. Rosen HR, Ribeiro RR, Weinberger L, Wolf S, Chung M, Gretch DR, Perelson AS. J Hepatol. 2002 Jul; 37(1):124-30.
- Increased turnover of T lymphocytes in HIV-1 infection and its reduction by antiretroviral therapy. Mohri H, Perelson AS, Tung K, Ribeiro RM, Ramratnam B, Markowitz M, Kost R, Hurley A, Weinberger L, Cesar D, Hellerstein MK, Ho DD. J Exp Med. 2001 Nov 05; 194(9):1277-87.
- Different turnover rate of hepatitis C virus clearance by different treatment regimen using interferon-beta. 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. J Hepatol. 2000 Aug; 33(2):313-22.
- Rapid turnover rate of hepatitis C virus clearance by the twice-a-day treatment regimen using interferon-beta. Yasushi Shiratori, As Perelson, L. Weinberger, F. Imazeki, O. Yokosuka, R. Nakata, M. Omata. Gastroenterology. 2000 Apr 1; 118(4):a1488.
- Dramatic rise in plasma viremia after CD8(+) T cell depletion in simian immunodeficiency virus-infected macaques. 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. J Exp Med. 1999 Mar 15; 189(6):991-8.