title: Modest human immunodeficiency virus coreceptor function of CXCR3 is strongly enhanced by mimicking the CXCR4 ligand binding pocket in the CXCR3 receptor.
abstract: The chemokine receptor CXCR3 can exhibit weak coreceptor function for several human immunodeficiency virus type 1 (HIV-1) and HIV-2 strains and clinical isolates. These viruses produced microscopically visible cytopathicity in U87.CD4.CXCR3 cell cultures, whereas untransfected (CXCR3-negative) U87.CD4 cells remained uninfected. Depending on the particular virus, the coreceptor efficiency of CXCR3 was 100- to >10,000-fold lower compared to that of CXCR4. A CXCR3 variant carrying the CXCR4 binding pocket was constructed by simultaneous lysine-to-alanine and serine-to-glutamate substitutions at positions 300 and 304 of the CXCR3 receptor. This mutant receptor (CXCR3[K300A, S304E]) showed markedly enhanced HIV coreceptor function compared to the wild-type receptor (CXCR3[WT]). Moreover, the CXCR4 antagonist AMD3100 exhibited antagonistic and anti-HIV activities in U87.CD4.CXCR3[K300A, S304E] cells but not in U87.CD4.CXCR3[WT] cells.
authors.affiliation: Rega Institute for Medical Research, Katholieke Universiteit Leuven, B-3000 Leuven, Belgium. sigrid.hatse@rega.kuleuven.be
authors.forename: Sigrid
authors.initials: S
authors.lastname: Hatse
authors.forename: Dana
authors.initials: D
authors.lastname: Huskens
authors.forename: Katrien
authors.initials: K
authors.lastname: Princen
authors.forename: Kurt
authors.initials: K
authors.lastname: Vermeire
authors.forename: Gary J
authors.initials: GJ
authors.lastname: Bridger
authors.forename: Erik
authors.initials: E
authors.lastname: De Clercq
authors.forename: Mette M
authors.initials: MM
authors.lastname: Rosenkilde
authors.forename: Thue W
authors.initials: TW
authors.lastname: Schwartz
authors.forename: Dominique
authors.initials: D
authors.lastname: Schols
mesh_terms: D000595:Amino Acid Sequence; D001665:Binding Sites; D045744:Cell Line, Tumor; D006678:HIV / Q000276:immunology* / Q000378:metabolism; D006801:Humans; D008024:Ligands; D018716:Molecular Mimicry / Q000276:immunology*; D008969:Molecular Sequence Data; D054367:Receptors, CXCR3; D019718:Receptors, CXCR4 / Q000737:chemistry / Q000276:immunology* / Q000378:metabolism*; D019707:Receptors, Chemokine / Q000737:chemistry / Q000235:genetics / Q000276:immunology* / Q000378:metabolism*; D015728:Receptors, HIV / Q000737:chemistry / Q000235:genetics / Q000276:immunology* / Q000378:metabolism
chemical_list: C515187:CXCR3 protein, human; D008024:Ligands; D054367:Receptors, CXCR3; D019718:Receptors, CXCR4; D019707:Receptors, Chemokine; D015728:Receptors, HIV