Modest human immunodeficiency virus coreceptor function of CXCR3 is strongly enhanced by mimicking the CXCR4 ligand binding pocket in the CXCR3 receptor.
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.
Hatse
Sigrid
S
Rega Institute for Medical Research, Katholieke Universiteit Leuven, B-3000 Leuven, Belgium. sigrid.hatse@rega.kuleuven.be
Huskens
Dana
D
Princen
Katrien
K
Vermeire
Kurt
K
Bridger
Gary J
GJ
De Clercq
Erik
E
Rosenkilde
Mette M
MM
Schwartz
Thue W
TW
Schols
Dominique
D
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
C515187:CXCR3 protein, human; D008024:Ligands; D054367:Receptors, CXCR3; D019718:Receptors, CXCR4; D019707:Receptors, Chemokine; D015728:Receptors, HIV