Rescue of HIV-1 receptor function through cooperation between different forms of the CCR5 chemokine receptor.
Interaction of the human immunodeficiency virus (HIV-1) envelope glycoproteins with the CCR5 chemokine receptor, a G-protein-coupled receptor, triggers a membrane fusion process and virus entry. Cooperation for HIV-1 receptor activity was observed when two forms of CCR5 were coexpressed, either the wild-type (WT) receptor and a defective mutant with deletion of the amino-terminal (NT) extracellular domain or the latter deltaNT mutant and a human-mouse CCR5 chimera bearing the NT domain from human CCR5. Cooperation was most efficient when the two forms of CCR5 were in a 1:1 ratio. It was not observed between the CCR5 deltaNT mutant and a chimeric receptor (5444) in which the NT domain of CCR5 was in the context of another G-protein-coupled receptor, the HIV-1 receptor CXCR4. These results suggested that physical association between two forms of CCR5 was required for their cooperation. Coimmunoprecipitation experiments in transfected cell lysates indeed showed that the deltaNT CCR5 mutant formed oligomeric complexes with the WT CCR5 or the HMMM chimera but not with the CXCR4-derived chimera 5444. These observations suggest that the formation of CCR5 oligomers is a constitutive process independent from activation by chemokine ligands. The interaction of HIV-1 with independent subunits of CCR5 oligomers could favor the local recruitment of fusiogenic proteins and the formation of a fusion pore.
Chelli
Maurice
M
Department of Cell Biology, Institut Cochin, INSERM U-567, CNRS Unité Mixté de Recherche 8404, Université Paris V-René Descartes, 75014 Paris, France.
Alizon
Marc
M
D000818:Animals; D015153:Blotting, Western; D002462:Cell Membrane / Q000378:metabolism; D005434:Flow Cytometry; D017353:Gene Deletion; D015497:HIV-1 / Q000378:metabolism*; D006367:HeLa Cells; D006801:Humans; D008024:Ligands; D008561:Membrane Fusion; D051379:Mice; D009154:Mutation; D010957:Plasmids / Q000378:metabolism; D011233:Precipitin Tests; D011485:Protein Binding; D017434:Protein Structure, Tertiary; D019713:Receptors, CCR5 / Q000378:metabolism*; D019718:Receptors, CXCR4 / Q000378:metabolism; D014162:Transfection
D008024:Ligands; D019713:Receptors, CCR5; D019718:Receptors, CXCR4