title: HIV-1 entry and macrophage inflammatory protein-1beta-mediated signaling are independent functions of the chemokine receptor CCR5.
abstract: The human immunodeficiency virus type 1 (HIV-1) requires the presence of specific chemokine receptors in addition to CD4 to enter its target cell. The chemokine receptor CCR5 is used by macrophage-tropic strains of HIV-1, which predominate during the asymptomatic stages of infection. Here we investigate whether the ability of CCR5 to signal in response to its beta-chemokine ligands is necessary or sufficient for viral entry. Three CCR5 mutants with little or no ability to mobilize calcium in response to macrophage inflammatory protein-1beta could nonetheless support HIV-1 entry and the early steps in the virus life cycle with efficiencies comparable with those of wild-type CCR5. Conversely, a chimeric receptor with the N terminus of CCR2 replacing that of CCR5 responded to macrophage inflammatory protein-1beta and MCP-1 but did not efficiently support viral entry. These results demonstrate that chemokine signaling and HIV-1 entry are separable functions of CCR5 and that only viral entry requires the N-terminal domain of CCR5.
authors.affiliation: Division of Human Retrovirology, Dana-Farber Cancer Institute, Department of Pathology, Harvard Medical School, Boston, Massachusetts 02115, USA.
authors.forename: M
authors.initials: M
authors.lastname: Farzan
authors.forename: H
authors.initials: H
authors.lastname: Choe
authors.forename: K A
authors.initials: KA
authors.lastname: Martin
authors.forename: Y
authors.initials: Y
authors.lastname: Sun
authors.forename: M
authors.initials: M
authors.lastname: Sidelko
authors.forename: C R
authors.initials: CR
authors.lastname: Mackay
authors.forename: N P
authors.initials: NP
authors.lastname: Gerard
authors.forename: J
authors.initials: J
authors.lastname: Sodroski
authors.forename: C
authors.initials: C
authors.lastname: Gerard
mesh_terms: D000818:Animals; D002460:Cell Line; D054407:Chemokine CCL4; D004285:Dogs; D015497:HIV-1 / Q000502:physiology*; D006801:Humans; D019402:Macrophage Inflammatory Proteins / Q000378:metabolism*; D008264:Macrophages / Q000378:metabolism* / Q000821:virology; D009154:Mutation; D019713:Receptors, CCR5; D018121:Receptors, Cytokine / Q000235:genetics / Q000378:metabolism*; D015728:Receptors, HIV / Q000235:genetics / Q000378:metabolism*; D015398:Signal Transduction; D014779:Virus Replication
chemical_list: D054407:Chemokine CCL4; D019402:Macrophage Inflammatory Proteins; D019713:Receptors, CCR5; D018121:Receptors, Cytokine; D015728:Receptors, HIV