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Vol. 13, Issue 2, 723-737, February 2002
*Institut de Recherche Interdisciplinaire en Biologie Humaine et
Nucléaire, CC-chemokine receptor 5 (CCR5) is the principal coreceptor
for macrophage-tropic strains of human immunodeficiency virus type 1 (HIV-1). We have generated a set of anti-CCR5 monoclonal
antibodies 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 regulated on activation normal T cell
expressed and secreted (RANTES), macrophage inflammatory
polypeptide-1Laboratoire de Neurophysiologie,
Service de Génétique Médicale, and
@Laboratoire de Cytologie et Cancérologie
Expérimentale, Université Libre de Bruxelles, B-1070
Brussels, Belgium; Institute for Animal Physiology,
University of Munich, 80539 Munich, Germany; §Euroscreen
s.a., B-1070 Brussels, Belgium; ¶Département de
Biologie Cellulaire, Institut Cochin de Génétique
Moléculaire, 75014 Paris, France; and #Medizinische
Poliklinik, University of Munich, 80336 Munich, Germany
, and Env binding, whereas MC-5 inhibited macrophage
inflammatory polypeptide-1 and Env but not RANTES binding. MC-6
induced signaling in different functional assays, suggesting that this
monoclonal antibody 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 that is distinct from that induced by the
receptor's agonists.
Online version of this article contains video material for
Figures 5-8. Online version available at www.molbiolcell.org.
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