Richard Koup, M.D.
Immunology Laboratory
Description of Research Program
The mission of the Immunology Laboratory (IML) is to investigate novel aspects of the cellular immune response to pathogens in support of the rational development of a vaccine against HIV and other lethal human viral pathogens. It is the goal of the IML to rapidly advance the latest information on ways of manipulating the immune response to HIV into practical applications in clinical trials of prophylactic and therapeutic vaccines. In support of this effort, we emphasize a detailed analysis of the strength, breadth, plasticity, phenotype, and functional characteristics of the cellular immune response to HIV during natural infection, and how it does or does not differ from the immune response during other viral infections or that are generated after vaccination.
One other aspect of the IML that is crucial to the overall success of the VRC is the appropriate monitoring and reporting of vaccine-induced immune responses in support of regulatory filings, for it is only through the appropriate measurement of a vaccine-induced immune response that an accurate correlate of immune protection will be determined. This requires a different operational structure from what is present in most research laboratories. Therefore, we have established an immunology core laboratory (IMC) that works in close association with the IML in advancing and improving ways of measuring immune responses to vaccines. The IML and IMC work to derive the maximum amount of information from clinical trials specimens.
The overall goals of the IML are accomplished through three projects. First, we investigate T cell immune correlates of protection from virus infection. This involves a detailed analysis of multiple T cell phenotypes and functions of antigen-specific immune responses to natural infection and vaccination with specific emphasis on identifying factors that are crucial to the control of viral replication. Once specific factors are identified, the laboratory seeks to manipulate the expression of these factors either therapeutically or during vaccination, in order to improve the immune response to HIV. The second project derives from our observation that HIV-specific, as compared to other antigen-specific, CD4+ T cells are a preferential target for HIV infection, and this leads to early decline in this important immune response to HIV soon after natural infection. This indicates that the phenotype or function of different CD4 T cells may affect their susceptibility to HIV infection. The laboratory therefore has a project to determine the factors associated with increased and decreased HIV susceptibility of antigen-specific T cells. Finally, while the primary focus of the VRC is to develop a prophylactic vaccine against HIV, there are reasons to be optimistic that vaccine-induced immune responses generated under the cover of HAART may lead to therapeutic benefit. We therefore have a third project to evaluate therapeutic vaccine efficacy in vivo.
Selected Publications
Petrovas C, DA Price, J Mattapallil, DR Ambrozak, V Cecchinato, C Geldemacher, M Vaccari, E Tryniszewska, E Gostick, M Roederer, DC Douek, SH Morgan, SJ Davis, G Franchini, and RA Koup. SIV-specific CD8+ T cells express high levels of PD-1 and cytokines but have impaired proliferation capacity in acute and chronic SIVmac251 infection. Blood 110:928-936,2007.
Loré K, WC Adams, MJE Havenga, ML Precopio, L Holterman, J Goudsmit, and RA Koup. Myeloid and plasmacytoid dendritic cells are susceptible to recombinant adenovirus vectors and stimulate polyfunctional memory T cell responses. J. Immunol. 179:1721-1729,2007.
Duvall MG, K Loré, H Blaak, DA Ambrozak, WC Adams, K Santos, C Geldmacher, JR Mascola, AJ McMichael, A Jaye, HC Whittle, SL Rowland-Jones, and RA Koup. Dendritic cells are less susceptible to human immunodeficiency virus type 2 (HIV-2) infection than HIV-1 infection. J. Virol. 81:13486-13498,2007.
Precopio ML, MR Betts, J Parrino, DA Price, E Gostick, DR Ambrozak, TE Asher, A Harari, G Pantaleo, R Bailer, BS Graham, M Roederer, and RA Koup. Immunization with vaccinia virus induces polyfunctional and phenotypically distinctive CD8+ T cell responses. J. Exp. Med. 204:1405-1416,2007.
Casazza JP, MR Betts, DA Price, ML Precopio, LE Ruff, JM Brenchley, M Roederer, DC Douek, and RA Koup. Acquisition of direct antiviral effector functions by CMV-specific CD4+ T lymphocytes with cellular maturation. J. Exp. Med. 203:2865-2877,2006.
Petrovas C, JP Casazza, JM Brenchley, DA Price, E Gostick, WC Adams, ML Precopio, T Schacker, M Roederer, DC Douek, and RA Koup. PD-1 is a regulator of virus-specific CD8+ T cell survival in HIV infection. J. Exp. Med. 203:2281-2292,2006.
Betts MR, MC Nason, SM West, SC De Rosa, SA Migueles, J Abraham, MM Lederman, JM Benito, PA Goepfert, M Connors, M Roederer, and RA Koup. HIV nonprogressors preferentially maintain highly functional HIV-specific CD8+ T cells. Blood 107: 4781-4789,2006.
Lore K, A Smed-Sorensen, J Vasudevan, JR Mascola, and RA Koup. Myeloid and plasmacytoid dendritic cells transfer HIV-1 preferentially to antigen-specific CD4+ T-cells. J. Exp. Med. 201:2023-2033,2005.
G Pantaleo and RA Koup. Correlates of immune protection in HIV-1 infection: What we know, what we don't know, what we should know. Nature Med. 10:806-810,2004.
Koup RA. Reconsidering early HIV treatment and supervised treatment interruptions. PLoS Med 1:e41,2004.
Lore K, Betts MR, Brenchley JM, Kuruppu J, Khojasteh S, Perfetto S, Roederer M, Seder RA, Koup RA. Toll-like receptor ligands modulate dendritic cells to augment cytomegalovirus- and HIV-1-specific T cell responses. J Immunol. 2003 Oct 15;171(8):4320-8.
Douek DC, Picker LJ, Koup RA. T cell dynamics in HIV-1 infection. Annu Rev Immunol. 2003;21:265-304. Epub 2001 Dec 19.
Douek DC, Brenchley JM, Betts MR, Ambrozak DR, Hill BJ, Okamoto Y, Casazza JP, Kuruppu J, Kunstman K, Wolinsky S, Grossman Z, Dybul M, Oxenius A, Price DA, Connors M, Koup RA. HIV preferentially infects HIV-specific CD4+ T cells. Nature. 2002 May 2;417(6884):95-8.
Douek DC, RA Vescio, MR Betts, JM Brenchley, BJ Hill, L Zhang, JR Berenson, RH Collins, and RA Koup. Assessment of thymic output in adults after haematopoietic stem-cell transplantation and prediction of T-cell reconstitution. Lancet 355:1875-1881,2000.
Douek DC, RD McFarland, PH Keiser, EA Gage, JM Massey, BF Haynes, MA Polis, AT Haase, MB Feinberg, JL Sullivan, BD Jamieson, JA Zack, LJ Picker, and RA Koup. Changes in thymic function with age and during the treatment of HIV infection. Nature 396:690-695,1998.
Gauduin M-C, PWHI Parren, R Weir, CF Barbas, DR Burton, and RA Koup. Passive immunization with a neutralizing human monoclonal antibody protects hu-PBL-SCID mice against challenge by primary isolates of HIV-1. Nature Medicine 3:1389-1393,1997.
Wolinsky SM, BTM Korber, A Neumann, M Daniels, KJ Kuntsman, AJ Whetsell, Y Cao, DD Ho, JT Safrit, and RA Koup. Adaptive evolution of human immunodeficiency virus type 1 during the natural course of infection. Science 272:537-542,1996.
Koup RA, JT Safrit, Y Cao, CA Andrews, G McLeod, W Borkowsky, C Farthing, and DD Ho. Temporal association of cellular immune responses with the initial control of viremia in primary HIV-1 syndrome. J. Virol. 68:4650-4655,1994
If you are interested in a Research Fellowship, please send your CV to:
Dr. Richard Koup
NIH/Vaccine Research Center
40 Convent Drive
Bldg. 40, Room 4500
Bethesda, MD 20892-3005
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