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Member Information
Una O'Doherty, MD, PhD
Assistant Professor, Department of Pathology and Laboratory Medicine
Office Phone:
Office Fax:
Email: unao@mail.med.upenn.edu
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Education:
Keywords: HIV-1 latency, resting T cells, dendritic cells, integration
Research and/or Clinical Interests:
We are studying the mechanism whereby HIV-1 establishes treatment-resistant latent infection by examining HIV-1 infection of T cells and dendritic cells in vitro using quantitative and imaging methods.
Summary:
The use of highly active antiretroviral therapy (HAART) for HIV-1 infection has led to impressive reductions in HIV-related morbidity and mortality in the developed world. Yet when HAART is stopped, viremia inevitably returns, usually to pre-treatment levels. HIV disease is not yet curable, because a reservoir of virus that resists both antiretroviral therapy and antiviral immune responses accumulates in infected individuals, even when HAART is started immediately after exposure. The virus in this reservoir is mostly in the form of integrated HIV-1 DNA (proviruses) in the nuclei of latently infected resting CD4+ T cells.
We have begun to study the mechanisms whereby HIV-1 establishes latent infection within resting T cells, with special emphasis on the role(s) that sub-maximal T cell activation by DCs and other APCs may play in the process. We are also interested in determining whether there is a subset of resting T cells that is more permissive to HIV-1 integration. Together, these studies promise to provide important new insights into the development of treatment-resistant viral reservoirs in HIV-infected patients, and might eventually lead to new forms of therapy.
Representative Publications:
O'Doherty U , Steinman RM, Peng M, Cameron PU, Gezelter S, Kopeloff I, Swiggard WJ, Pope M, Bhardwaj N. Dendritic cells freshly isolated from human blood express CD4 and mature into typical immunostimulatory dendritic cells after culture in monocyte-conditioned medium. J. Exp. Med. 178: 1067-1078 (1993).
O'Doherty U , Peng M, g ezelter S, Swiggard WJ, Betjes M, Bhardwaj N, Steinman RM. Human blood contains two subsets of dendritic cells, one immunologically mature, and the other immature. Immunology. 82: 487-493 (1994).
Cameron PU, Lowe MG, Crowe SM, O'Doherty U , Pope M, Gezelter S, Steinman RM. Susceptibility of dendritic cells to HIV-1 infection in vitro . J. Leukocyte. Biol. 56: 257-265 (1994).
Yamaguchi Y, O'Doherty U , Peng M, Steinman RM. Difficulties in obtaining monoclonal antibodies to subsets of human leukocytes, using neonatal tolerance induction in mice. J. Immunol. Methods. 181(1): 115-24 (1995).
Granelli-Piperno A, Moser B, Pope M, Chen D, Wei Y, Isdell F, O'Doherty U , Paxton W, Koup R, Mojsov S, Bhardwaj N, Clark-Lewis I, Baggiolini M, Steinman RM. Efficient interaction of HIV-1 with purified dendritic cells via multiple chemokine receptors. J. Exp .Med. 184: 2433-2438 (1996).
O'Doherty U , Ignatius R, Bhardwaj N, Pope M. Generation of monocyte-derived dendritic cells from precursors in rhesus macaque blood. J. Immunol. Methods . 207: 185-194 (1997).
Ignatius R, Isdell F, O'Doherty U , Pope M. Dendritic cells from skin and blood of macaques both promote SIV replication with T cells from different anatomical sites. J. Med. Primatology. 27 (2-3):121-8 (1998).
Hu J, Pope M, Brown C, O'Doherty U , Miller CJ. Immunophenotypic characterization of simian immunodeficiency virus-infected dendritic cells in cervix, vagina, and draining lymph nodes of rhesus monkeys. Laboratory Investigation. 78(4): 435-51 (1998).
Hu J, Miller CJ, O'Doherty U , Marx PA, Pope M. The dendritic cell-T cell milieu of the lymphoid tissue of the tonsil provides a locale in which SIV can reside and propagate at chronic stages of infection. AIDS Res. Hum. Retroviruses . 15(14): 1305-14 (1999).
O'Doherty U , Swiggard WJ, and Malim MH. Human Immunodeficiency Virus type 1 spinoculation enhances infection through virus binding. J. Virol. 74(21): 10074-10080 (2000).
Lee B, Leslie G, Soilleux E, O'Doherty U , Baik S, Levroney E, Flummerfelt K, Swiggard W, Coleman N, Malim M, Doms RW. Cis-expression of DC-SIGN allows for more efficient HIV/SIV entry via CD4 and coreceptor. J. Virol. 75(24):12028-38 (2001).
O'Doherty U, Swiggard WJ, Jeyakumar D, McGain D, and Malim MH. A sensitive, quantitative assay for HIV-1 integration. J. Virol. 76(21) 10,942-10,950 (2002).
