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A more recent version of this article appeared on February 1, 2002
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Submitted on March 21, 2001
Revised on October 26, 2001
Accepted on November 19, 2001
1 Institut de Recherche Interdisciplinaire en Biologie Humaine et Nucléaire
2 Laboratoire de Neurophysiologie
3 Institute for Animal Physiology, University of Munich, 80539 Munich, Germany
4 Euroscreen s.a., B-1070 Bruxelles, Belgium
5 Département de Biologie Cellulaire, Institut Cochin de Génétique Moléculaire, 75014 Paris, France
6 Institut de Recherche Interdisciplinaire en Biologie Humaine et Nucléaire, and Service de Génétique Médicale, Université Libre de Bruxelles, B-1070 Bruxelles, Belgium
7 Medizinische Poliklinik, University of Munich, 80336 Munich, Germany
8 Institut de Recherche Interdisciplinaire en Biologie Humaine et Nucléaire; and Laboratoire de Cytologie et Cancérologie Expérimentale, Université Libre de Bruxelles, B-1070 Bruxelles, Belgium
* Corresponding author. E-mail address: mparment{at}ulb.ac.be.
CC-chemokine receptor 5 (CCR5) is the principal coreceptor for macrophage-tropic strains of human immunodeficiency virus type I (HIV-1). We have generated a set of anti-CCR5 monoclonal antibodies (MAbs) and characterized them in terms of epitope recognition, competition with chemokine binding, receptor activation and trafficking, and coreceptor activity. MC-4, MC-5 and MC-7 mapped to the amino-terminal domain, MC-1 to the second extracellular loop, and MC-6 to a conformational epitope covering multiple extracellular domains. MC-1 and MC-6 inhibited RANTES, MIP-1ß and Env binding, whereas MC-5 inhibited MIP-1ß and Env but not RANTES binding. MC-6 induced signaling in different functional assays, suggesting that this MAb stabilizes an active conformation of CCR5. Flow cytometry and real time confocal microscopy showed that MC-1 promoted strong CCR5 endocytosis. MC-1 but not its monovalent isoforms induced an increase in the transfer of energy between CCR5 molecules. Also, its monovalent isoforms bound efficiently, but did not internalize the receptor. In contrast, MC-4 did not prevent RANTES binding or subsequent signaling, but inhibited its ability to promote CCR5 internalization. These results suggest the existence of multiple active conformations of CCR5 and indicate that CCR5 oligomers are involved in an internalization process which is distinct from that induced by the receptor's agonists.
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