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

faculty photo
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 Pathology & Laboratory Medicine
University of Pennsylvania
265 John Morgan Building
3620 Hamilton Walk
Philadelphia, PA 19104-6082
Office: (215) 573-7273
Fax: (215) 573-2348
Education:
B.S. (Biochemistry)
Barnard College, New York, NY - cum laude, 1987.
Ph.D.
The Rockefeller University, New York, NY, Advisors: Drs. Nina Bhardwaj and Ralph M. Steinman, 1994.
M.D.
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 for 2008-2009
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
Luis Agosto - graduate student
Matt Pace - graduate student
Erin Graf - graduate student

Selected Publications

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.

Graf EH, Pace MJ, Peterson BA, Lynch LJ, Chukwulebe SB, Mexas AM, Shaheen F, Martin JN, Deeks SG, Connors M, Migueles S A, O’Doherty U: Gag-positive reservoir cells are susceptible to HIV-specific cytotoxic T lymphocyte mediated clearance PLOS ONE accepted, 2013.

Mexas Angela M, Graf Erin H, Pace Matthew J, Yu Jianqing J, Papasavvas Emmanouil, Azzoni Livio, Busch Michael P, Di Mascio Michele, Foulkes Andrea S, Migueles Stephen A, Montaner Luis J, O'Doherty Una: Concurrent measures of total and integrated HIV DNA monitor reservoirs and ongoing replication in eradication trials. AIDS (London, England) 26(18): 2295-306, Nov 2012.

Mendoza D, Johnson SA, Peterson BA, Natarajan V, Salgado M, Dewar RL, Burbelo PD, Doria-Rose NA, Graf EH, Greenwald, JH, Hodge, JN, Thompson, WL, Cogliano, NA, Chairez CL, Rehm, CA, Jones S, Hallahan CW, Kovacs JA, Sereti I, Sued O, Peel SA, O'Connell R J, O'Doherty U, Chun TW, Connors M, Migueles SA: Comprehensive analysis of unique cases with extraordinary control over HIV replication. Blood 119(20): 4645-55, 2012.

Pace MJ, Graf EH, Agosto LM, Mexas AM, Brady T, Male F, Bushman FD, O'Doherty U: Directly infected resting CD4+T Cells can produce HIV Gag without spreading infection in a model of HIV latency. PLoS Pathogens 8(7):e1002818, 2012.

Graf EH, Mexas AM, Yu JJ, Shaheen F, Liszewski M, DiMascio M, Migueles SA, Connors M, O'Doherty U: Elite Suppressors harbor low levels of integrated HIV DNA and high levels of 2-LTR circular HIV DNA compared to HIV+ patients on and off HAART. PloS Pathogens 7(2), February 2011.

Pace M, Agosto LM, O'Doherty U: R5 HIV Env and VSV-G cooperate to mediate fusion to naive CD4+T cells. Journal of Virology 85(1): 644-8, Jan 2011.

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Last updated: 01/14/2014
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