title: Multiple extracellular domains of CCR-5 contribute to human immunodeficiency virus type 1 entry and fusion.
abstract: Human immunodeficiency virus type 1 (HIV-1) entry is governed by the interaction of the viral envelope glycoprotein (Env) with its receptor. The HIV-1 receptor is composed of two molecules, the CD4 binding receptor and a coreceptor. The seven-membrane-spanning chemokine receptor CCR-5 is one of the coreceptors used by primary isolates of HIV-1. We demonstrate that the mouse homolog of CCR-5 (mCCR-5) does not function as an HIV-1 coreceptor. A set of chimeras of human CCR-5 and mCCR-5 was studied for Env-induced cell fusion and HIV-1 infection. Using the HIV-1ADA envelope glycoprotein in a syncytium formation assay, we show that replacement of any fragment containing extracellular domains of mCCR-5 by its human counterparts is sufficient to allow Env-induced fusion. Conversely, replacement of any fragment containing human extracellular domains by its murine counterpart did not lead to coreceptor function loss. These results show that several domains of CCR-5 participate in coreceptor function. In addition, using a panel of primary nonsyncytium-inducing and syncytium-inducing isolates that use CCR-5 or both CXCR-4 and CCR-5 as coreceptors, we show that the latter dual-tropic isolates are less tolerant to changes in CCR-5 than strains with a more restricted coreceptor use. Thus, different strains are likely to have different ways of interacting with the CCR-5 coreceptor.
authors.affiliation: Chester Beatty Laboratories, Institute of Cancer Research, London, United Kingdom. laurent@icr.ac.uk
authors.forename: L
authors.initials: L
authors.lastname: Picard
authors.forename: G
authors.initials: G
authors.lastname: Simmons
authors.forename: C A
authors.initials: CA
authors.lastname: Power
authors.forename: A
authors.initials: A
authors.lastname: Meyer
authors.forename: R A
authors.initials: RA
authors.lastname: Weiss
authors.forename: P R
authors.initials: PR
authors.lastname: Clapham
mesh_terms: D000595:Amino Acid Sequence; D000818:Animals; D001665:Binding Sites; D002415:Cats; D002461:Cell Line, Transformed; D015699:HIV Envelope Protein gp120 / Q000235:genetics / Q000378:metabolism; D015497:HIV-1 / Q000302:isolation & purification / Q000378:metabolism* / Q000502:physiology; D006367:HeLa Cells; D006801:Humans; D008561:Membrane Fusion; D051379:Mice; D008969:Molecular Sequence Data; D019713:Receptors, CCR5; D018121:Receptors, Cytokine / Q000737:chemistry / Q000235:genetics / Q000378:metabolism*; D015728:Receptors, HIV / Q000737:chemistry / Q000235:genetics / Q000378:metabolism*; D011993:Recombinant Fusion Proteins / Q000235:genetics / Q000378:metabolism; D013329:Structure-Activity Relationship; D014407:Tumor Cells, Cultured
chemical_list: D015699:HIV Envelope Protein gp120; D019713:Receptors, CCR5; D018121:Receptors, Cytokine; D015728:Receptors, HIV; D011993:Recombinant Fusion Proteins