title: HIV-1 infection through the CCR5 receptor is blocked by receptor dimerization.
abstract: The identification of the chemokine receptors as receptors for HIV-1 has boosted interest in these molecules, raising expectations for the development of new strategies to prevent HIV-1 infection. The discovery that chemokines block HIV-1 replication has focused attention on identifying their mechanism of action. Previous studies concluded that this inhibitory effect may be mediated by steric hindrance or by receptor down-regulation. We have identified a CCR5 receptor-specific mAb that neither competes with the chemokine for binding nor triggers signaling, as measured by Ca(2+) influx or chemotaxis. The antibody neither triggers receptor down-regulation nor interferes with the R5 JRFL viral strain gp120 binding to CCR5, but blocks HIV-1 replication in both in vitro assays using peripheral blood mononuclear cells as HIV-1 targets, as well as in vivo using human peripheral blood mononuclear cell-reconstituted SCID (severe combined immunodeficient) mice. Our evidence shows that the anti-CCR5 mAb efficiently prevents HIV-1 infection by inducing receptor dimerization. Chemokine receptor dimerization also is induced by chemokines and is required for their anti-HIV-1 activity. In addition to providing a molecular mechanism through which chemokines block HIV-1 infection, these results illustrate the prospects for developing new tools that possess HIV-1 suppressor activity, but lack the undesired inflammatory side effects of the chemokines.
authors.affiliation: Department of Immunology and Oncology, Centro Nacional de Biotecnologia, Universidad Autónoma de Madrid, Campus de Cantoblanco, E-28049, Madrid, Spain.
authors.forename: A J
authors.initials: AJ
authors.lastname: Vila-Coro
authors.forename: M
authors.initials: M
authors.lastname: Mellado
authors.forename: A
authors.initials: A
authors.lastname: Martín de Ana
authors.forename: P
authors.initials: P
authors.lastname: Lucas
authors.forename: G
authors.initials: G
authors.lastname: del Real
authors.forename: C
authors.initials: C
authors.lastname: Martínez-A
authors.forename: J M
authors.initials: JM
authors.lastname: Rodríguez-Frade
mesh_terms: D000818:Animals; D000911:Antibodies, Monoclonal / Q000276:immunology; D002460:Cell Line; D018946:Chemokine CCL5 / Q000378:metabolism; D019281:Dimerization; D015536:Down-Regulation; D015658:HIV Infections / Q000378:metabolism*; D015497:HIV-1; D006801:Humans; D051379:Mice; D016513:Mice, SCID; D011485:Protein Binding; D019713:Receptors, CCR5 / Q000276:immunology / Q000378:metabolism*
chemical_list: D000911:Antibodies, Monoclonal; D018946:Chemokine CCL5; D019713:Receptors, CCR5