Many viruses have the ability to undergo a developmental decision to either replicate in the cell or enter a long-lived transcriptionally silent state (i.e. a dormant or “latent” state). The resulting latent reservoirs are the greatest barrier to treatment and eradication of many viruses. We aim to define the transcriptional 'master circuits' that viruses use to regulate the developmental ‘switch’ between viral latency and active viral replication.
Our lab employs both quantitative single-cell imaging and computational approaches (mathematical modeling) to probe the kinetics of these gene-regulatory circuits in live cells. We have a long-standing interest in how transcriptional fluctuations (‘noise’) regulate viral fate decisions. We are also actively translating our basic science discoveries to engineer novel classes of antiviral therapies.
We are pioneering a new class of anti-HIV molecular parasites called Therapeutic Interfering Particles, or TIPs (Metzger et al., 2011). TIPs replicate only in HIV-infected cells and parasitize HIV molecular componentry to reduce viral load and infectivity. As a result of this piggybacking, TIPs could transmit along the same transmission routes as HIV and have the potential to be ‘resistance-proof’ single-administration therapies and could automatically target those most in need of therapy to reduce HIV burden, especially in resource-limited settings such as sub-Saharan Africa.
We study viruses such as HIV and Herpesviruses (e.g. CMV) not only because they are significant human health problems but also because viruses are ideal model systems to probe cell-fate determination: they allow for rapid testing and have a long history of driving seminal discoveries in biology (e.g. the demonstration of the DNA->RNA->protein central dogma, discovery of codons, and the discovery of oncogenes).
Dar RD, Hosmane NN, Arkin MR, Siliciano RF, Weinberger LS. "Screening for noise in gene expression identifies drug synergies." Science 20 June 2014: Vol. 344 no. 6190 pp. 1392-1396.
Weinberger AD and Weinberger LS. "Stochastic fate selection in HIV-infected patients." Cell, 2013, Oct 24; 153(3), 497-499.
Rouzine IM, Weinberger LS. "Design requirements for interfering particles to maintain coadaptive stability with HIV-1." Journal of Virology. 2013 Feb;87(4):2081-93.
Teng MW, Bolovan-Fritts C, Dar RD, Womack A, Shenk T, Simpson ML, Weinberger LS. “An Endogenous Accelerator for Viral Gene Expression Provides a Fitness Advantage.” Cell, December 2012. 151;7:1569-1580,
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 11.
Singh A, Razooky BS, Dar RD, Weinberger LS."Dynamics of protein noise can distinguish between alternate sources of gene-expression variability." Nature Molecular Systems Biology. 2012. Aug 28;8:607
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 on a Chip. 2012. Oct 2;12(12):4305-4312.
Metzger V, Lloyd-Smith JO, Weinberger LS."Autonomous Targeting of Infectious Superspreaders using Engineered Transmissable Therapies." PLoS Computational Biology. 2011 Mar;7(3):e1002015.
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." Biophysical Journal. 2010 Apr 21;98(8):L32-4.
Singh A, Weinberger LS, "Stochastic gene expression as a molecular switch for viral latency." Curr Opin Microbiol, 2009 Jul 10; 12(4):460-6.
Weinberger LS, Dar RD, Simpson ML, "Transient-mediated fate determination in a transcriptional circuit of HIV." Nature Genetics, 2008 Apr; 40(4):466-70.
Weinberger LS, Shenk T, "An HIV feedback resistor: auto-regulatory circuit deactivator and noise buffer." PLoS Biology, 2007 Jan; 5(1):e9.
Weinberger LS, Burnett JC, Toettcher JE, Arkin AP, Schaffer DV, "Stochastic gene expression in a lentiviral positive-feed back loop: HIV-1 Tat fluctuations drive phenotypic diversity." Cell, 2005 Jul; 122(2):169-82.
Weinberger LS, Schaffer DV, Arkin AP, "Theoretical design of a gene therapy to prevent AIDS but not human immunodeficiency virus type 1 infection." Journal of Virology, 2003 Sep; 77(18):10028-36.