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Research Laboratories
Immunology Laboratory
Richard Koup, M.D.

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 operates under GLP conditions within the VRC structure and 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 (vaccines that are known to be protective and those that are currently in testing). The second project derives from our observation that HIV-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. Because this process is likely to be mediated at the dendritic cell - T cell interface during the stimulation of HIV-specific CD4+ T cells, and could undermine the ability of a vaccine-induced HIV-specific CD4+ T cell response to effectively fight HIV infection, we have established a project to investigate dendritic cell biology in HIV infection. 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:

1. 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.
2. Koup RA. Reconsidering early HIV treatment and supervised treatment interruptions. PLoS Med 1:e41,2004.
3. Price DA, SM West, MR Betts, LE Ruff, JM Brenchley, DR Ambrozak, Y Edghill-Smith, MJ Kuroda, D Bogdan, K Kunstman, NL Letvin, G Franchini, SM Wolinsky, RA Koup, and DC Douek. T-cell receptor recognition motifs govern immune escape patterns in acute SIV infection. Immunity 21:793-803,2004.
4. Wolint P, MR Betts, RA Koup, and A Oxenius. Immediate cytotoxicity but not degranulation distinguishes effector and memory subsets of CD8+ T cells. J. Exp. Med. 199:925-36,2004.
5. Betts MR, DA Price, JM Brenchley, K Lore, FJ Guenaga, A Smed-Sorenson, DR Ambrozak, SA Migueles, M Connors, M Roederer, DC Douek, and RA Koup. The functional profile of primary human antiviral CD8+ T cell effector activity is dictated by cognate peptide concentration. J. Immunol. 172:6407-6417,2004.
6. Brenchley JM, Hill BJ, Ambrozak DR, Price DA, Guenaga FJ, Casazza JP, Kuruppu J, Yazdani J, Migueles SA, Connors M, Roederer M, Douek DC, Koup RA. T-cell subsets that harbor human immunodeficiency virus (HIV) in vivo: implications for HIV pathogenesis. J Virol. 2004 Feb;78(3):1160-8.
7. 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.
8. Sullivan NJ, Geisbert TW, Geisbert JB, Xu L, Yang ZY, Roederer M, Koup RA, Jahrling PB, Nabel GJ. Accelerated vaccination for Ebola virus haemorrhagic fever in non-human primates. Nature. 2003 Aug 7;424(6949):681-4.
9. Douek DC, Picker LJ, Koup RA. T cell dynamics in HIV-1 infection. Annu Rev Immunol. 2003;21:265-304. Epub 2001 Dec 19.
10. Brenchley JM, Karandikar NJ, Betts MR, Ambrozak DR, Hill BJ, Crotty LE, Casazza JP, Kuruppu J, Migueles SA, Connors M, Roederer M, Douek DC, Koup RA. Expression of CD57 defines replicative senescence and antigen-induced apoptotic death of CD8+ T cells. Blood. 2003 Apr 1;101(7):2711-20. Epub 2002 Nov 14.
11. Little SJ, Holte S, Routy JP, Daar ES, Markowitz M, Collier AC, Koup RA, Mellors JW, Connick E, Conway B, Kilby M, Wang L, Whitcomb JM, Hellmann NS, Richman DD. Antiretroviral-drug resistance among patients recently infected with HIV. N Engl J Med. 2002 Aug 8;347(6):385-94.
12. 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.
13. Okamoto Y, Douek DC, McFarland RD, Koup RA. Effects of exogenous interleukin-7 on human thymus function. Blood. 2002 Apr 15;99(8):2851-8.
14. Douek DC, Betts MR, Brenchley JM, Hill BJ, Ambrozak DR, Ngai KL, Karandikar NJ, Casazza JP, Koup RA. A novel approach to the analysis of specificity, clonality, and frequency of HIV-specific T cell responses reveals a potential mechanism for control of viral escape. J Immunol. 2002 Mar 15;168(6):3099-104.
15. Douek DC, Betts MR, Hill BJ, Little SJ, Lempicki R, Metcalf JA, Casazza J, Yoder C, Adelsberger JW, Stevens RA, Baseler MW, Keiser P, Richman DD, Davey RT, Koup RA. Evidence for increased T cell turnover and decreased thymic output in HIV infection. J Immunol. 2001 Dec 1;167(11):6663-8.
16. Betts MR, JP Casazza, BA Patterson, S Waldrop, W Trigona, T-M Fu, F Kern, LJ Picker, and RA Koup. Putative immunodominant HIV-specific CD8+ T-cell responses cannot be predicted by MHC class I haplotype. J. Virol. 74:9144-9151, 2000.
17. 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.
18. Jamieson BD, DC Douek, S Killian, LE Hultin, DD Scripture-Adams, JV Giorgi, D Marelli, RA Koup, and JA Zack. Generation of functional thymocytes in the human adult. Immunity 10:569-575,1999.
19. Pitcher CJ, C Quittner, DM Peterson, M Connors, RA Koup, VC Maino, and LJ Picker. HIV-1 specific CD4+ T cells are detectable in most individuals with active HIV-1 infection, but decline with prolonged viral suppression. Nature Medicine 5:518-525,1999.
20. 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.
21. 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.
22. 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.
23. 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