title: The two human CXCR4 isoforms display different HIV receptor activities: consequences for the emergence of X4 strains.
abstract: CXCR4 is a chemokine receptor that plays key roles with its specific ligand, CXCL12, in stem cell homing and immune trafficking. It is also used as a coreceptor by some HIV-1 strains (X4 strains), whereas other strains (R5 strains) use an alternative coreceptor, CCR5. X4 strains mainly emerge at late stages of the infection and are linked to disease progression. Two isoforms of this coreceptor have been described in humans: CXCR4-A and CXCR4-B, corresponding to an unspliced and a spliced mRNA, respectively. In this study, we show that CXCR4-B, but not CXCR4-A, mediates an efficient HIV-1 X4 entry and productive infection. Yet, the chemotactic activity of CXCL12 on both isoforms was similar. Furthermore, HIV-R5 infection favored CXCR4-B expression over that of CXCR4-A. In vitro infection with an R5 strain increased CXCR4-B/CXCR4-A mRNA ratio in PBMCs, and this ratio correlated with HIV RNA plasma level in R5-infected individuals. In addition, the presence of the CXCR4-B isoform favored R5 to X4 switch more efficiently than did CXCR4-A in vitro. Hence, the predominance of CXCR4-B over CXCR4-A expression in PBMCs was linked to the ability of circulating HIV-1 strains to use CXCR4, as determined by genotyping. These data suggest that R5 to X4 switch could be favored by R5 infection-induced overexpression of CXCR4-B. Finally, we achieved a specific small interfering RNA-mediated knockdown of CXCR4-B. This represents a proof of concept for a possible gene-therapeutic approach aimed at blocking the HIV coreceptor activity of CXCR4 without knocking down its chemotactic activity.
authors.affiliation: Institut de Génétique Humaine, Unité Propre de Recherche 1142 du Centre National de la Recherche Scientifique, 34396 Montpellier Cedex 5, France;
authors.forename: Charline
authors.initials: C
authors.lastname: Duquenne
authors.affiliation: Infectious Diseases Department, Montpellier University Hospital, 34295 Montpellier Cedex 5, France; Unité Mixte Internationale 233, Institut de Recherche pour le Développement-Université Montpellier 1, 34294 Montpellier Cedex 5, France;
authors.forename: Christina
authors.initials: C
authors.lastname: Psomas
authors.affiliation: Institut de Génétique Humaine, Unité Propre de Recherche 1142 du Centre National de la Recherche Scientifique, 34396 Montpellier Cedex 5, France;
authors.forename: Sandrine
authors.initials: S
authors.lastname: Gimenez
authors.affiliation: Institut de Génétique Humaine, Unité Propre de Recherche 1142 du Centre National de la Recherche Scientifique, 34396 Montpellier Cedex 5, France;
authors.forename: Adeline
authors.initials: A
authors.lastname: Guigues
authors.affiliation: Microbiology Department, Nîmes University Hospital, 30029 Nîmes Cedex 9, France;
authors.forename: Marie-Josée
authors.initials: MJ
authors.lastname: Carles
authors.affiliation: Infectious Diseases Department, Nîmes University Hospital, 30029 Nîmes Cedex 9, France;
authors.forename: Claudine
authors.initials: C
authors.lastname: Barbuat
authors.affiliation: Microbiology Department, Nîmes University Hospital, 30029 Nîmes Cedex 9, France; Faculté de Médecine, Université Montpellier 1, 34967 Montpellier Cedex 2, France; INSERM U1047, 30908 Nîmes Cedex 9, France;
authors.forename: Jean-Philippe
authors.initials: JP
authors.lastname: Lavigne
authors.affiliation: Infectious Diseases Department, Nîmes University Hospital, 30029 Nîmes Cedex 9, France; Faculté de Médecine, Université Montpellier 1, 34967 Montpellier Cedex 2, France; INSERM U1047, 30908 Nîmes Cedex 9, France;
authors.forename: Albert
authors.initials: A
authors.lastname: Sotto
authors.affiliation: Infectious Diseases Department, Montpellier University Hospital, 34295 Montpellier Cedex 5, France; Unité Mixte Internationale 233, Institut de Recherche pour le Développement-Université Montpellier 1, 34294 Montpellier Cedex 5, France; Faculté de Médecine, Université Montpellier 1, 34967 Montpellier Cedex 2, France;
authors.forename: Jacques
authors.initials: J
authors.lastname: Reynes
authors.affiliation: Unité Mixte de Recherche 5235, Centre National de la Recherche Scientifique-Université Montpellier 2, 34095 Montpellier, France; and.
authors.forename: Paul
authors.initials: P
authors.lastname: Guglielmi
authors.affiliation: Institut de Génétique Humaine, Unité Propre de Recherche 1142 du Centre National de la Recherche Scientifique, 34396 Montpellier Cedex 5, France;
authors.forename: Clément
authors.initials: C
authors.lastname: Mettling
authors.affiliation: Institut de Génétique Humaine, Unité Propre de Recherche 1142 du Centre National de la Recherche Scientifique, 34396 Montpellier Cedex 5, France;
authors.forename: Vincent
authors.initials: V
authors.lastname: François
authors.affiliation: Institut de Génétique Humaine, Unité Propre de Recherche 1142 du Centre National de la Recherche Scientifique, 34396 Montpellier Cedex 5, France; Faculté de Médecine, Université Montpellier 1, 34967 Montpellier Cedex 2, France; Immunology Department, Nîmes University Hospital, 30029 Nîmes Cedex 9, France pcorbeau@igh.cnrs.fr.
authors.forename: Pierre
authors.initials: P
authors.lastname: Corbeau
mesh_terms: D045744:Cell Line, Tumor; D054377:Chemokine CXCL12 / Q000276:immunology; D015658:HIV Infections / Q000276:immunology; D015497:HIV-1 / Q000145:classification / Q000235:genetics / Q000378:metabolism*; D006367:HeLa Cells; D006801:Humans; D020033:Protein Isoforms / Q000096:biosynthesis / Q000235:genetics / Q000276:immunology; D034622:RNA Interference; D034741:RNA, Small Interfering; D019713:Receptors, CCR5 / Q000276:immunology; D019718:Receptors, CXCR4 / Q000235:genetics / Q000276:immunology*; D015728:Receptors, HIV / Q000235:genetics / Q000276:immunology*; D053585:Virus Attachment; D053586:Virus Internalization; D014779:Virus Replication / Q000276:immunology
chemical_list: C515255:CXCL12 protein, human; C527276:CXCR4 protein, human; D054377:Chemokine CXCL12; D020033:Protein Isoforms; D034741:RNA, Small Interfering; D019713:Receptors, CCR5; D019718:Receptors, CXCR4; D015728:Receptors, HIV