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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:
- 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.
- 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.
- 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.
- 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.
- 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.
- 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.
- 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.
- Douek DC, Picker LJ, Koup RA. T
cell dynamics in HIV-1 infection. Annu Rev Immunol.
2003;21:265-304. Epub 2001 Dec 19.
- 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.
- 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.
- 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.
- 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.
- 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.
- 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.
- 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.
- 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.
- 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.
- 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.
- 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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