Leor Weinberger

Last updated
Leor Weinberger
Born1975
Toronto, Canada
Citizenship United States
Alma mater University of California, Berkeley (PhD)
Princeton University (Lewis Thomas Fellow)
Known forviral latency programs, Therapeutic Interfering Particles (TIPs), stochastic fluctuations/bet-hedging
AwardsPew Scholar
Sloan Fellow
Blavatnik Fellow
Keck awardee
TED speaker
NIH Director's Pioneer Award
NIH Director's New Innovator Award
NIH Avant-Garde Award for HIV Research
Scientific career
Fields Virology, Synthetic Biology
Institutions University of California, San Francisco
Gladstone Institutes

Leor S. Weinberger is an American virologist and quantitative biologist. He is credited with discovering the HIV virus latency circuit, which provided the first experimental evidence that stochastic fluctuations ('noise') in gene expression are used for cell fate decisions. [1] [2] He has also pioneered the concept of therapeutic interfering particles, or “TIPs”, which are resistance-proof antivirals. [3] His TED talk [4] on this novel antiviral approach 20 years in the making has been called a "highlight" [5] of TED and received a standing ovation from the live audience. Weinberger's TIP discovery was profiled in Science magazine [6] and by Carl Zimmer in The New York Times [7] .

Contents

Weinberger is currently the William and Ute Bowes Distinguished Professor of Virology, director of the Gladstone Center for Cell Circuitry, professor of pharmaceutical chemistry, and professor of biochemistry and biophysics at Gladstone Institutes/University of California, San Francisco [8] He is the only person to ever win the NIH Director’s Pioneer Award, NIH/NIDA Avant Garde Award, and NIH Director's New Innovator Award. [9] [10] [11]

Education and career

Weinberger received his undergraduate degree in biophysics from University of Maryland, College Park in 1998. [12] He completed his PhD in Biophysics, with a focus on HIV, from University of California, Berkeley in 2004. [8] [13] He received postdoctoral training at Princeton University as a Lewis Thomas Fellow, working with Thomas Shenk and David Botstein. [8]

After completing his fellowship at Princeton, Weinberger joined the University of California, San Diego, as an assistant professor for the Department of Chemistry and Biochemistry. [12] Afterwards, he moved to the University of California, San Francisco (UCSF) in an associate professor in biochemistry and biophysics before transitioning to Gladstone Institutes, the non-profit research institution associated with UCSF. [8] Weinberger is now the director of the Gladstone UCSF Center for Cell Circuitry and Bowes Distinguished Professor, and he retains his professorships at UCSF in pharmaceutical chemistry and biochemistry and biophysics. [8]

Research

Areas of focus

Weinberger and his lab specialize in virology, with a specific focus on HIV/AIDS, human cytomegalovirus, and herpesvirus. [8] As stated on their website, the lab uses “mathematical & experimental approaches to decode the regulatory principles viruses use to select between alternate fates” and develop therapeutic targets and antiviral strategies based on those principles. [14]

Major discoveries

Weinberger and his lab have been credited with the discovery of HIV’s intrinsic decision circuit. [1] Their 2005 paper in Cell showed that stochastic fluctuations in gene expression, or ‘noise’ can drive cell fate decisions enabling viral latency, which is recognized as a primary barrier to HIV cure. [15] The lab has since been able to identify similar stochastic processes in other viruses, such as a kind of herpesvirus called human cytomegalovirus, as published in a 2020 paper. [16] Weinberger and his lab are looking for ways to target the latency reservoir of viruses as a form of treatment. [17]

Weinberger's work has been referred to as "part of what some scientists are calling a 'renaissance' in viral therapy" by the San Francisco Chronicle . [18] According to Wired, Weinberger has pioneered research to combat HIV by creating "therapeutic interfering particles" or "TIPs". Weinberger first began testing this concept when he was in graduate school at Berkeley studying the biophysics of HIV. [19] As described on Weinberger’s lab website and in a pre-print research article, TIPs are engineered deletion mutants designed to piggyback on a virus and deprive the virus of replication material, thus reducing viral load. [14] [20] TIPs replicate and co-evolve with a virus, making it a treatment that solves what Weinberger has called a “fundamental mismatch” between viruses and treatment: viruses evolve, vaccines do not. [19] [21] TIPs also have the capacity to transmit along viral transmission routes, harnessing the power of virus “super spreaders” and transmitting the treatment to resource-limited and remote populations like communities in South Africa. [19] TIP research has been supported by the Department of Defense DARPA program, NIH/NIDA, and recently the Joint Warfighter Medical Research Program for a clinical trial. [22] [9] [23]

Awards and honors

Weinberger holds numerous patents for inventing novel antiviral medicines. [24] Weinberger was named a Pew Scholar in the Biomedical Sciences in 2008, [25] an Alfred P. Sloan Foundation Research Fellow in 2011, [26] and a Keck Awardee. [27] He served on the Bill & Melinda Gates Foundation Innovation review panel, and his research has been widely published in Science, Nature, and Cell. [27] [9] He is the only person to win the NIH Director’s Pioneer, Avant Garde, and New Innovator Awards. [9] [10] [11]

Related Research Articles

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<span class="mw-page-title-main">Defective interfering particle</span>

Defective interfering particles (DIPs), also known as defective interfering viruses, are spontaneously generated virus mutants in which a critical portion of the particle's genome has been lost due to defective replication or non-homologous recombination. The mechanism of their formation is presumed to be as a result of template-switching during replication of the viral genome, although non-replicative mechanisms involving direct ligation of genomic RNA fragments have also been proposed. DIPs are derived from and associated with their parent virus, and particles are classed as DIPs if they are rendered non-infectious due to at least one essential gene of the virus being lost or severely damaged as a result of the defection. A DIP can usually still penetrate host cells, but requires another fully functional virus particle to co-infect a cell with it, in order to provide the lost factors.

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A therapeutic interfering particle is an antiviral preparation that reduces the replication rate and pathogenesis of a particular viral infectious disease. A therapeutic interfering particle is typically a biological agent (i.e., nucleic acid) engineered from portions of the viral genome being targeted. Similar to Defective Interfering Particles (DIPs), the agent competes with the pathogen within an infected cell for critical viral replication resources, reducing the viral replication rate and resulting in reduced pathogenesis. But, in contrast to DIPs, TIPs are engineered to have an in vivo basic reproductive ratio (R0) that is greater than 1 (R0>1). The term "TIP" was first introduced in 2011 based on models of its mechanism-of-action from 2003. Given their unique R0>1 mechanism of action, TIPs exhibit high barriers to the evolution of antiviral resistance and are predicted to be resistance proof. Intervention with therapeutic interfering particles can be prophylactic (to prevent or ameliorate the effects of a future infection), or a single-administration therapeutic (to fight a disease that has already occurred, such as HIV or COVID-19). Synthetic DIPs that rely on stimulating innate antiviral immune responses (i.e., interferon) were proposed for influenza in 2008 and shown to protect mice to differing extents but are technically distinct from TIPs due to their alternate molecular mechanism of action which has not been predicted to have a similarly high barrier to resistance. Subsequent work tested the pre-clinical efficacy of TIPs against HIV, a synthetic DIP for SARS-CoV-2 (in vitro), and a TIP for SARS-CoV-2 (in vivo).

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Human Immunodeficiency Virus (HIV) has the capability to enter a latent stage of infection where it exists as a dormant provirus in CD4+ T-cells. Most latently infected cells are resting memory T cells, however a small fraction of latently infected cells isolated from HIV patients are naive CD4 T cells.

References

  1. 1 2 Weinberger, Leor (July 29, 2005). "Stochastic Gene Expression in a Lentiviral Positive- Feedback Loop: HIV-1 Tat Fluctuations Drive Phenotypic Diversity". Cell. 122 (2): 169–82. arXiv: q-bio/0608002 . doi:10.1016/j.cell.2005.06.006. PMID   16051143. S2CID   8061716.
  2. ↑ Howard Hughes Medical Institute, July 29, 2005. http://www.hhmi.org/news/random-gene-expression-may-drive-hiv-hiding
  3. ↑ Mosher, Dave. "Piggyback Virus Could Curb HIV Pandemic". Wired. ISSN   1059-1028 . Retrieved 2023-08-11.
  4. ↑ Weinberger, Leor (26 October 2020), Can we create vaccines that mutate and spread? , retrieved 2020-12-01
  5. ↑ "In the time of COVID-19, TEDMED still thrills". 12 March 2020.
  6. ↑ Bold new strategy to suppress HIV passes first test (Report). 2024-08-08. doi:10.1126/science.zfj15w4.
  7. ↑ "Engineered Virus Steals Proteins From H.I.V., Pointing to New Therapy, Carl Zimmer". 2024-08-08. Retrieved 2024-11-06.
  8. 1 2 3 4 5 6 "leor.weinberger@gladstone.ucsf.edu". gladstone.org. Retrieved 2020-11-13.
  9. 1 2 3 4 Abuse, National Institute on Drug (2020-06-23). "Avant-Garde Award Program for HIV/AIDS and Substance Use Disorder Research". National Institute on Drug Abuse. Retrieved 2020-11-13.
  10. 1 2 National Institute of Health, April 2015. http://commonfund.nih.gov/arra/newinnovator
  11. 1 2 National Institute of Health, April 2015. http://commonfund.nih.gov/pioneer/Recipients13
  12. 1 2 "Leor Weinberger | UCSF Profiles". profiles.ucsf.edu. Retrieved 2020-11-13.
  13. ↑ "Keynote Speakers – UC Berkeley Center for Computational Biology Retreat 2019". ccb.berkeley.edu. Retrieved 2020-11-13.
  14. 1 2 "Weinberger Lab Gladstone / University of California, San Francisco". Weinberger Lab. Retrieved 2020-11-13.
  15. ↑ Siliciano, Robert F.; Greene, Warner C. (September 2011). "HIV Latency". Cold Spring Harbor Perspectives in Medicine. 1 (1): a007096. doi:10.1101/cshperspect.a007096. ISSN   2157-1422. PMC   3234450 . PMID   22229121.
  16. ↑ Institutes, Gladstone. "Herpesviruses Hedge Their Bets to Optimize Survival". www.prnewswire.com (Press release). Retrieved 2020-11-13.
  17. ↑ Tan and Elledge Genome Medicine 2014, 6:55. http://genomemedicine.com/content/6/1/55
  18. ↑ Erin Allday, January 23rd, 2013. "Viruses engineered to attack themselves", San Francisco Chronicle. http://www.sfgate.com/health/article/Viruses-engineered-to-attack-themselves-4233236.php
  19. 1 2 3 Weinberger, Leor (26 October 2020). "Transcript of "Can we create vaccines that mutate and spread?"". www.ted.com. Retrieved 2020-11-13.
  20. ↑ Tanner, Elizabeth J.; Jung, Seung-Yong; Glazier, Joshua; Thompson, Cassandra; Zhou, Yuqi; Martin, Benjamin; Son, Hye-In; Riley, James L.; Weinberger, Leor S. (2019-10-30). "Discovery and Engineering of a Therapeutic Interfering Particle (TIP): a combination self-renewing antiviral". bioRxiv: 820456. doi:10.1101/820456. S2CID   208600143.
  21. ↑ Weinberger, Leor. "Evolvable 'Resistance-Proof' Therapies".{{cite journal}}: Cite journal requires |journal= (help)
  22. ↑ "To Fight a Virus, Get a Virus: Military Bets on Mutant Pathogen". Bloomberg.com. 2016-07-14. Retrieved 2020-11-13.
  23. ↑ "Joint Warfighter Medical Research Program, FY20 Military Medical Research and Development Award - Human Subjects/Sample Acquisition with Clinical Trial Option, Congressionally Directed Medical Research Programs". cdmrp.army.mil. Retrieved 2020-12-01.
  24. ↑ "Google Patents". patents.google.com. Retrieved 2020-11-13.
  25. ↑ Pew Charitable Trusts, April 2015. "Pew Scholars Directory - Weinberger, Leor S". Archived from the original on 2015-04-02. Retrieved 2015-02-20.
  26. ↑ Alfred P. Sloan Foundation, April 2015. "Archived copy" (PDF). Archived from the original (PDF) on 2014-04-11. Retrieved 2014-03-27.{{cite web}}: CS1 maint: archived copy as title (link)
  27. 1 2 "Leor Weinberger".
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