Una O'Doherty, M.D.Ph.D.

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Associate Professor of Pathology and Laboratory Medicine at the Hospital of the University of Pennsylvania
Department: Pathology and Laboratory Medicine
Graduate Group Affiliations

Contact information
Department of Laboratory Medicine and Therapeutic Pathology
Division of Transfusion Medicine
University of Pennsylvania
705 Stellar Chance Laboratory
422 Curie Blvd.
Philadelphia, PA 19104
Office: (215) 573-7273
Fax: (215) 573-5369
B.S. (Biochemistry)
Barnard College, New York, NY - cum laude, 1987.
The Rockefeller University, New York, NY, Advisors: Drs. Nina Bhardwaj and Ralph M. Steinman, 1994.
Cornell University Medical College, New York, NY, 1995.
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Description of Research Expertise

Research Interests
HIV-1 latency.

Key words: HIV, latency, reservoirs, dendritic cells, viral pathogenesis, proviral integration, retrovirus, virology, T cell activation, resting T cells.

Description of Research
Highly active anti-retroviral therapy can clear the blood of HIV-1 virions. But, despite long-term suppression of virus, when the drugs are stopped the virus returns. Thus, reservoirs of latent, treatment-resistant HIV-1 exist in infected individuals and are a major barrier to cure. Our lab has developed an in vitro model of HIV-1 latency. We use quantitative and imaging methods to study how HIV-1 establishes latent infection in resting CD4+ T cells.

Current dogma holds that latent HIV-1 infection occurs only when T cells are activated. Our findings challenge this. Using novel quantitative assays we made three discoveries about latent HIV-1 infection in CD4+ T cells. One, HIV-1 can integrate into resting CD4+ T cells. Two, the T cells bearing integrated HIV-1 genomes do not produce new virions unless stimulated. Three after stimulation a percentage of these cells produce virus. Thus, in our system HIV-1 establishes latent infection in resting T cells in the absence of activating stimuli. We now want to determine if reservoirs form more efficiently in the presence of subtle stimuli and if reservoirs form preferentially in subsets of resting T cells that are more permissive for HIV-1 integration. We are attempting to quantify the contribution of memory and naive cells to reservoirs in vivo. Finally, we are interested to determine how reservoirs are maintained in vivo. To study this, we are first developing assays that can sensitively detect ongoing replication.

In addition, a new focus in our lab is to enhance transduction of resting CD4+ T cells with gene therapy vectors based on the HIV genome.

In summary, we have developed an in vitro model of HIV-1 latency and our studies promise to provide new insights into reservoir formation in HIV-1 infected individuals and may eventually lead to novel therapies.

Rotation Projects
1. Measure the percentage of resting T cells that contain provirus (integrated viral DNA) in HIV-infected individuals in various CD4+ T cell subpopulations including memory and naïve subsets to understand the contribution of both of these cell types to reservoirs.
2. Measure total, linear and integrated HIV DNA to determine if ongoing replication occurs on HAART.
3. Quantify the frequency of multiply infected cells after single round infection of resting CD4+ T cells to determine if hypersusceptible cells exist among naive and memory cells.
4. Determine the susceptibilities of other primary WBC (dendritic cells and progenitor cells to HIV integration).

Lab personnel:

Jenny Yu - Research Specialist
Angela Mexas - Postdoctoral fellow

Selected Publications

DeMaster Laura K, Liu Xiaohe, VanBelzen D Jake, Trinité Benjamin, Zheng Lingjie, Agosto Luis M, Migueles Stephen A, Connors Mark, Sambucetti Lidia, Levy David N, Pasternak Alexander O, O'Doherty Una: A subset of CD4/CD8 double negative T cells expresses HIV proteins in patients on ART. Journal of virology Nov 2015.

Pasternak Alexander O, DeMaster Laura K, Kootstra Neeltje A, Reiss Peter, O'Doherty Una, Berkhout Ben: Minor Contribution of Host-HIV Readthrough Transcripts to the Level of HIV Cell-associated gag RNA. Journal of virology Nov 2015.

Procopio Francesco Andrea, Fromentin Rémi, Kulpa Deanna A, Brehm Jessica H, Bebin Anne-Gaelle, Strain Matthew C, Richman Douglas D, O'Doherty Una, Palmer Sarah, Hecht Frederick M, Hoh Rebecca, Barnard Richard J O, Miller Michael D, Hazuda Daria J, Deeks Steven G, Sékaly Rafick-Pierre, Chomont Nicolas: A Novel Assay to Measure the Magnitude of the Inducible Viral Reservoir in HIV-infected Individuals. EBioMedicine 2(8): 872-81, Aug 2015.

Cockerham Leslie R, Siliciano Janet D, Sinclair Elizabeth, O'Doherty Una, Palmer Sarah, Yukl Steven A, Strain Matt C, Chomont Nicolas, Hecht Frederick M, Siliciano Robert F, Richman Douglas D, Deeks Steven G: CD4+ and CD8+ T Cell Activation Are Associated with HIV DNA in Resting CD4+ T Cells. PloS one 9(10): e110731, Oct 2014.

Garfall A L, Dougherty A L, Vogl D T, Weiss B M, Cohen A D, Mick R, O'Doherty U, Stadtmauer E A: Association between mobilization regimen and PFS after auto-SCT for multiple myeloma. Bone marrow transplantation 49(11): 1439-41, Jul 2014.

De Spiegelaere Ward, Malatinkova Eva, Lynch Lindsay, Van Nieuwerburgh Filip, Messiaen Peter, O'Doherty Una, Vandekerckhove Linos: Quantification of integrated HIV DNA by repetitive-sampling Alu-HIV PCR on the basis of poisson statistics. Clinical chemistry 60(6): 886-95, Jun 2014.

Pace Matthew J, Graf Erin H, O'Doherty Una: HIV 2-long terminal repeat circular DNA is stable in primary CD4+T Cells. Virology 441(1): 18-21, Jun 2013.

Eriksson S, Graf EH, Dahl V, Strain MC, Yukl SA, Lysenko ES, Bosch RJ, Lai J, Chioma S, Emad F, Abdel-Mohsen M, Hoh R, Hecht F, Hunt P, Somsouk M, Wong J, Johnston R, Siliciano RF, Richman DD, O'Doherty U, Palmer S, Deeks SG, Siliciano JD: Comparative Analysis of Measures of Viral Reservoirs in HIV-1 Eradication Studies. PLoS pathogens 9(2): e1003174, Feb 2013.

Brady T, Kelly BJ, Male F, Roth S, Bailey Aubrey, Malani N, Gijsbers R, O'Doherty U, Bushman FD: Quantitation of HIV DNA integration: Effects of differential integration site distributions on Alu-PCR assays. Journal of virological methods 189(1): 53-57, Jan 2013.

Azzoni Livio, Foulkes Andrea S, Papasavvas Emmanouil, Mexas Angela M, Lynn Kenneth M, Mounzer Karam, Tebas Pablo, Jacobson Jeffrey M, Frank Ian, Busch Michael P, Deeks Steven G, Carrington Mary, O'Doherty Una, Kostman Jay, Montaner Luis J: Pegylated Interferon alfa-2a monotherapy results in suppression of HIV type 1 replication and decreased cell-associated HIV DNA integration. The Journal of infectious diseases 207(2): 213-22, Jan 2013.

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Last updated: 01/24/2016
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