title: Targeting spare CC chemokine receptor 5 (CCR5) as a principle to inhibit HIV-1 entry.
abstract: CCR5 binds the chemokines CCL3, CCL4, and CCL5 and is the major coreceptor for HIV-1 entry into target cells. Chemokines are supposed to form a natural barrier against human immunodeficiency virus, type 1 (HIV-1) infection. However, we showed that their antiviral activity is limited by CCR5 adopting low-chemokine affinity conformations at the cell surface. Here, we investigated whether a pool of CCR5 that is not stabilized by chemokines could represent a target for inhibiting HIV infection. We exploited the characteristics of the chemokine analog PSC-RANTES (N-α-(n-nonanoyl)-des-Ser(1)-[l-thioprolyl(2), l-cyclohexylglycyl(3)]-RANTES(4-68)), which displays potent anti-HIV-1 activity. We show that native chemokines fail to prevent high-affinity binding of PSC-RANTES, analog-mediated calcium release (in desensitization assays), and analog-mediated CCR5 internalization. These results indicate that a pool of spare CCR5 may bind PSC-RANTES but not native chemokines. Improved recognition of CCR5 by PSC-RANTES may explain why the analog promotes higher amounts of β-arrestin 2·CCR5 complexes, thereby increasing CCR5 down-regulation and HIV-1 inhibition. Together, these results highlight that spare CCR5, which might permit HIV-1 to escape from chemokines, should be targeted for efficient viral blockade.
authors.affiliation: From the INSERM U1108, Viral Pathogenesis Unit, Department of Virology, Institut Pasteur, 75015 Paris, France.
authors.forename: Jun
authors.initials: J
authors.lastname: Jin
authors.affiliation: From the INSERM U1108, Viral Pathogenesis Unit, Department of Virology, Institut Pasteur, 75015 Paris, France, the Université Paris Diderot, Sorbonne Paris Cité, Cellule Pasteur, rue du Docteur Roux, 75015 Paris, France.
authors.forename: Philippe
authors.initials: P
authors.lastname: Colin
authors.affiliation: From the INSERM U1108, Viral Pathogenesis Unit, Department of Virology, Institut Pasteur, 75015 Paris, France.
authors.forename: Isabelle
authors.initials: I
authors.lastname: Staropoli
authors.affiliation: the Institut Cochin, Université Paris Descartes, CNRS UMR 8104, INSERM U1016, 75014 Paris, France.
authors.forename: Evelyne
authors.initials: E
authors.lastname: Lima-Fernandes
authors.affiliation: From the INSERM U1108, Viral Pathogenesis Unit, Department of Virology, Institut Pasteur, 75015 Paris, France.
authors.forename: Cécile
authors.initials: C
authors.lastname: Ferret
authors.affiliation: From the INSERM U1108, Viral Pathogenesis Unit, Department of Virology, Institut Pasteur, 75015 Paris, France.
authors.forename: Arzu
authors.initials: A
authors.lastname: Demir
authors.affiliation: the Institut Cochin, Université Paris Descartes, CNRS UMR 8104, INSERM U1016, 75014 Paris, France.
authors.forename: Sophie
authors.initials: S
authors.lastname: Rogée
authors.affiliation: the Department of Pathology and Immunology, University of Geneva, 1211 Geneva 4, Switzerland, and.
authors.forename: Oliver
authors.initials: O
authors.lastname: Hartley
authors.affiliation: the Institut Cochin, Université Paris Descartes, CNRS UMR 8104, INSERM U1016, 75014 Paris, France.
authors.forename: Clotilde
authors.initials: C
authors.lastname: Randriamampita
authors.affiliation: the Institut Cochin, Université Paris Descartes, CNRS UMR 8104, INSERM U1016, 75014 Paris, France.
authors.forename: Mark G H
authors.initials: MG
authors.lastname: Scott
authors.affiliation: the Institut Cochin, Université Paris Descartes, CNRS UMR 8104, INSERM U1016, 75014 Paris, France.
authors.forename: Stefano
authors.initials: S
authors.lastname: Marullo
authors.affiliation: the Unité de Biologie des Interactions Cellulaires, Institut Pasteur, 75015 Paris, France.
authors.forename: Nathalie
authors.initials: N
authors.lastname: Sauvonnet
authors.affiliation: From the INSERM U1108, Viral Pathogenesis Unit, Department of Virology, Institut Pasteur, 75015 Paris, France.
authors.forename: Fernando
authors.initials: F
authors.lastname: Arenzana-Seisdedos
authors.affiliation: From the INSERM U1108, Viral Pathogenesis Unit, Department of Virology, Institut Pasteur, 75015 Paris, France.
authors.forename: Bernard
authors.initials: B
authors.lastname: Lagane
authors.affiliation: From the INSERM U1108, Viral Pathogenesis Unit, Department of Virology, Institut Pasteur, 75015 Paris, France, anne.brelot@pasteur.fr.
authors.forename: Anne
authors.initials: A
authors.lastname: Brelot
mesh_terms: D019380:Anti-HIV Agents / Q000494:pharmacology*; D019390:Arrestins / Q000378:metabolism; D018946:Chemokine CCL5 / Q000494:pharmacology*; D057809:HEK293 Cells; D015497:HIV-1 / Q000187:drug effects* / Q000502:physiology*; D006801:Humans; D042541:Intracellular Space / Q000187:drug effects / Q000378:metabolism; D019713:Receptors, CCR5 / Q000378:metabolism*; D015398:Signal Transduction / Q000187:drug effects; D053586:Virus Internalization / Q000187:drug effects*; D000071560:beta-Arrestin 2; D000071557:beta-Arrestins
chemical_list: C000605254:ARRB2 protein, human; D019380:Anti-HIV Agents; D019390:Arrestins; D018946:Chemokine CCL5; C492865:RANTES, N(alpha)-(n-nonanoyl)-desSer(1)-(thioproline(2),cyclohexylglycine(3))-; D019713:Receptors, CCR5; D000071560:beta-Arrestin 2; D000071557:beta-Arrestins
keywords: Antiviral Agent; CCR5; Conformation; Endocytosis; G-protein-coupled Receptor (GPCR); HIV-1 Protease; Virus Entry