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Departments of
*
Oncology,
Experimental Pathology, Bristol-Myers Squibb Pharmaceutical Research Institute, Princeton, NJ 08543; and, Department of Microbiology, Bristol-Myers Squibb Pharmaceutical Research Institute, Wallingford, CT 06492
The CC-chemokine receptor CCR5 has been shown to be the major coreceptor for HIV-1 entry into cells, and humans with homozygous mutation in the ccr5 gene are highly resistant to HIV-1 infection, despite the existence of many other HIV-1 coreceptors. To investigate the physiologic function of CCR5 and to understand the cellular mechanisms of these clinical observations, we generated a CCR5-deficient mouse model (ccr5-/-) by targeted deletion of the ccr5 gene. We found that although developed normally in a pathogen-free environment, CCR5-deficient mice showed reduced efficiency in clearance of Listeria infection and exsert a protective effect aganist LPS-induced endotoxemia, reflecting a partial defect in macrophage function. In addition, CCR5-deficient mice had an enhanced delayed-type hypersensitivity reaction and increased humoral responses to T cell-dependent antigenic challenge, indicating a novel role of CCR5 in down-modulating T cell-dependent immune response.
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P. G. Andres, P. L. Beck, E. Mizoguchi, A. Mizoguchi, A. K. Bhan, T. Dawson, W. A. Kuziel, N. Maeda, R. P. MacDermott, D. K. Podolsky, et al. Mice with a Selective Deletion of the CC Chemokine Receptors 5 or 2 Are Protected from Dextran Sodium Sulfate-Mediated Colitis: Lack of CC Chemokine Receptor 5 Expression Results in a NK1.1+ Lymphocyte-Associated Th2-Type Immune Response in the Intestine J. Immunol., June 15, 2000; 164(12): 6303 - 6312. [Abstract] [Full Text] [PDF]
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N. Sato, W. A. Kuziel, P. C. Melby, R. L. Reddick, V. Kostecki, W. Zhao, N. Maeda, S. K. Ahuja, and S. S. Ahuja Defects in the Generation of IFN-{gamma} Are Overcome to Control Infection with Leishmania donovani in CC Chemokine Receptor (CCR) 5-, Macrophage Inflammatory Protein-1{alpha}-, or CCR2-Deficient Mice J. Immunol., November 15, 1999; 163(10): 5519 - 5525. [Abstract] [Full Text] [PDF]
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G. B. Huffnagle, L. K. McNeil, R. A. McDonald, J. W. Murphy, G. B. Toews, N. Maeda, and W. A. Kuziel Cutting Edge: Role of C-C Chemokine Receptor 5 in Organ-Specific and Innate Immunity to Cryptococcus neoformans J. Immunol., November 1, 1999; 163(9): 4642 - 4646. [Abstract] [Full Text] [PDF]
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S. J. O'Brien, M. Menotti-Raymond, W. J. Murphy, W. G. Nash, J. Wienberg, R. Stanyon, N. G. Copeland, N. A. Jenkins, J. E. Womack, and J. A. Marshall Graves The Promise of Comparative Genomics in Mammals Science, October 15, 1999; 286(5439): 458 - 481. [Abstract] [Full Text]
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Z. Wang, B. Lee, J. L. Murray, F. Bonneau, Y. Sun, V. Schweickart, T. Zhang, and S. C. Peiper CCR5 HIV-1 Coreceptor Activity. ROLE OF COOPERATIVITY BETWEEN RESIDUES IN N-TERMINAL EXTRACELLULAR AND INTRACELLULAR DOMAINS J. Biol. Chem., October 1, 1999; 274(40): 28413 - 28419. [Abstract] [Full Text] [PDF]
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X. Deng, H. Ueda, S. B. Su, W. Gong, N. M. Dunlop, J.-L. Gao, P. M. Murphy, and J. M. Wang A Synthetic Peptide Derived From Human Immunodeficiency Virus Type 1 gp120 Downregulates the Expression and Function of Chemokine Receptors CCR5 and CXCR4 in Monocytes by Activating the 7-Transmembrane G-Protein-Coupled Receptor FPRL1/LXA4R Blood, August 15, 1999; 94(4): 1165 - 1173. [Abstract] [Full Text] [PDF]
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R. S. Klein, K. C. Williams, X. Alvarez-Hernandez, S. Westmoreland, T. Force, A. A. Lackner, and A. D. Luster Chemokine Receptor Expression and Signaling in Macaque and Human Fetal Neurons and Astrocytes: Implications for the Neuropathogenesis of AIDS J. Immunol., August 1, 1999; 163(3): 1636 - 1646. [Abstract] [Full Text] [PDF]
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O. M. Z. Howard, A.-K. Shirakawa, J. A. Turpin, A. Maynard, G. J. Tobin, M. Carrington, J. J. Oppenheim, and M. Dean Naturally Occurring CCR5 Extracellular and Transmembrane Domain Variants Affect HIV-1 Co-receptor and Ligand Binding Function J. Biol. Chem., June 4, 1999; 274(23): 16228 - 16234. [Abstract] [Full Text] [PDF]
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 J.-L. Gao, E. J. Lee, and P. M. Murphy Impaired Antibacterial Host Defense in Mice Lacking the N-formylpeptide Receptor J. Exp. Med., February 15, 1999; 189(4): 657 - 662. [Abstract] [Full Text] [PDF]
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D. P. Andrew, M.-s. Chang, J. McNinch, S. T. Wathen, M. Rihanek, J. Tseng, J. P. Spellberg, and C. G. Elias III STCP-1 (MDC) CC Chemokine Acts Specifically on Chronically Activated Th2 Lymphocytes and Is Produced by Monocytes on Stimulation with Th2 Cytokines IL-4 and IL-13 J. Immunol., November 1, 1998; 161(9): 5027 - 5038. [Abstract] [Full Text] [PDF]
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R. K. Ganju, S. A. Brubaker, R. D. Chernock, S. Avraham, and J. E. Groopman beta -Chemokine Receptor CCR5 Signals through SHP1, SHP2, and Syk J. Biol. Chem., June 2, 2000; 275(23): 17263 - 17268. [Abstract] [Full Text] [PDF]
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K. Maeda, K. Yoshimura, S. Shibayama, H. Habashita, H. Tada, K. Sagawa, T. Miyakawa, M. Aoki, D. Fukushima, and H. Mitsuya Novel Low Molecular Weight Spirodiketopiperazine Derivatives Potently Inhibit R5 HIV-1 Infection through Their Antagonistic Effects on CCR5 J. Biol. Chem., September 7, 2001; 276(37): 35194 - 35200. [Abstract] [Full Text] [PDF]
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T. Dragic, A. Trkola, D. A. D. Thompson, E. G. Cormier, F. A. Kajumo, E. Maxwell, S. W. Lin, W. Ying, S. O. Smith, T. P. Sakmar, et al. A binding pocket for a small molecule inhibitor of HIV-1 entry within the transmembrane helices of CCR5 PNAS, May 9, 2000; 97(10): 5639 - 5644. [Abstract] [Full Text] [PDF]
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B. G. Dorner, A. Scheffold, M. S. Rolph, M. B. Huser, S. H. E. Kaufmann, A. Radbruch, I. E. A. Flesch, and R. A. Kroczek MIP-1alpha , MIP-1beta , RANTES, and ATAC/lymphotactin function together with IFN-gamma as type 1 cytokines PNAS, April 30, 2002; 99(9): 6181 - 6186. [Abstract] [Full Text] [PDF]
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J. M. Strizki, S. Xu, N. E. Wagner, L. Wojcik, J. Liu, Y. Hou, M. Endres, A. Palani, S. Shapiro, J. W. Clader, et al. SCH-C (SCH 351125), an orally bioavailable, small molecule antagonist of the chemokine receptor CCR5, is a potent inhibitor of HIV-1 infection in vitro and in vivo PNAS, October 23, 2001; 98(22): 12718 - 12723. [Abstract] [Full Text] [PDF]
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