This proposal outlines a 5 year plan for the training of this candidate for an academic career as a Transfusion Medicine Virologist. She has completed 3 years of formal residency training in Clinical Pathology, and is now working in her sponsor's laboratory. Her research interests center upon HIV-1 molecular pathogenesis, in particular, the regulation of HIV-1 replication in resting and activated T cells. She has a strong background in cellular immunology, having received a Ph.D. in this field under Dr. Ralph M. Steinman in the Department of Cellular Physiology and Immunology at The Rockefeller University. This experience poises her to investigate viral infection in primary leukocytes; however, she lacks the experience in HIV molecular biology necessary to attack questions of regulation independently. An integrative research and training program for the Principal Investigator is being established within the Department of Pathology. The candidate's sponsors are Michael H. Malim and Francisco Gonzalez- Scarano, both recognized authorities on molecular HIV-1 pathogenesis. In addition, an advisory board of prominent scientists will insure the candidate's development. While all steps of the virus life cycle offer opportunities for regulation, it is her intention to examine events that occur between fusion at the plasma membrane and integration of viral DNA into cellular DNA. One reason for pursuing this path is that these aspects of HIV replication have received little attention to date. In addition, there is evidence that infection of T cells is blocked at an early step, since 1 in 100 T cells from infected individuals contain HIV DNA, but only 1 in 10,000 contain integrated HIV DNA. A greater understanding of these critical early steps is likely to identify novel virus-host cell interactions that may serve as future targets for therapeutic consideration. She describes three specific aims: (1) measuring HIV uptake by quiescent T cells; (2) examining the kinetics of viral transport to and through nuclear pore complexes in quiescent and activated T cells; and (3) determining the changing composition of post-entry nucleoprotein complexes in resting and activated T cells. These unprecedented studies promise to provide critical new insights into the HIV disease process. Concurrently, Dr. O'Doherty will acquire the expertise necessary for her to become an independent Transfusion Medicine Virologist.

National Institute of Health (NIH)
National Heart, Lung, and Blood Institute (NHLBI)
Clinical Investigator Award (CIA) (K08)
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Special Emphasis Panel (ZHL1-CSR-K (F2))
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University of Pennsylvania
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Swiggard, William J; Baytop, Clifford; Yu, Jianqing J et al. (2005) Human immunodeficiency virus type 1 can establish latent infection in resting CD4+ T cells in the absence of activating stimuli. J Virol 79:14179-88
Swiggard, William J; O'Doherty, Una; McGain, David et al. (2004) Long HIV type 1 reverse transcripts can accumulate stably within resting CD4+ T cells while short ones are degraded. AIDS Res Hum Retroviruses 20:285-95
O'Doherty, Una; Swiggard, William J; Jeyakumar, Deepa et al. (2002) A sensitive, quantitative assay for human immunodeficiency virus type 1 integration. J Virol 76:10942-50
Lee, B; Leslie, G; Soilleux, E et al. (2001) cis Expression of DC-SIGN allows for more efficient entry of human and simian immunodeficiency viruses via CD4 and a coreceptor. J Virol 75:12028-38
O'Doherty, U; Swiggard, W J; Malim, M H (2000) Human immunodeficiency virus type 1 spinoculation enhances infection through virus binding. J Virol 74:10074-80