The CC chemokine I-309 inhibits CCR8-dependent infection by diverse HIV-1 strains.
Using a chemokine receptor model based on known receptor sequences, we identified several members of the seven transmembrane domain G-protein superfamily as potential chemokine receptors. The orphan receptor ChemR1, which has recently been shown to be a receptor for the CC chemokine I-309, scored very high in our model. We have confirmed that I-309, but not a number of other chemokines, can induce a transient Ca2+ flux in cells expressing CCR8. In addition, the human erythroleukemic cell line K562 responded chemotactically in a dose-responsive manner to this chemokine. Since several chemokine receptors have been shown to be required as coreceptors for HIV-1 infection, we asked whether human immunodeficiency virus type 1 (HIV-1) could efficiently utilize CCR8. Here we show that the CCR8 receptor can serve as a coreceptor for diverse T-cell tropic, dual-tropic, and macrophage-tropic HIV-1 strains and that I-309 was a potent inhibitor of HIV-1 envelope-mediated cell-cell fusion and virus infection. Furthermore, we show by flow cytometry and immunohistochemistry that antibodies generated against the CCR8 receptor amino-terminal peptide cross-reacted with U-87 MG cells stably expressing CCR8, THP-1 cells, HL-60 cells, and human monocytes, a target cell for HIV-1 infectivity in vivo.
Horuk
R
R
Departments of Immunology, Pharmacology, and Cell Biology, Berlex Biosciences, Richmond, California 94804, USA. Horuk@crl.com
Hesselgesser
J
J
Zhou
Y
Y
Faulds
D
D
Halks-Miller
M
M
Harvey
S
S
Taub
D
D
Samson
M
M
Parmentier
M
M
Rucker
J
J
Doranz
B J
BJ
Doms
R W
RW
D000595:Amino Acid Sequence; D002460:Cell Line; D054402:Chemokine CCL1; D019742:Chemokines, CC; D002630:Chemotactic Factors / Q000737:chemistry / Q000235:genetics / Q000378:metabolism; D018076:DNA, Complementary; D015497:HIV-1 / Q000145:classification / Q000472:pathogenicity*; D006801:Humans; D007150:Immunohistochemistry; D008969:Molecular Sequence Data; D054401:Receptors, CCR8; D019707:Receptors, Chemokine / Q000235:genetics / Q000378:metabolism*; D015728:Receptors, HIV / Q000737:chemistry / Q000378:metabolism*; D017386:Sequence Homology, Amino Acid; D013045:Species Specificity
C065971:CCL1 protein, human; C103330:CCR8 protein, human; D054402:Chemokine CCL1; D019742:Chemokines, CC; D002630:Chemotactic Factors; D018076:DNA, Complementary; D054401:Receptors, CCR8; D019707:Receptors, Chemokine; D015728:Receptors, HIV