The lymphocyte chemoattractant SDF-1 is a ligand for LESTR/fusin and blocks HIV-1 entry.
Chemokines are chemotactic cytokines that activate and direct the migration of leukocytes. There are two subfamilies, the CXC and the CC chemokines. We recently found that the CXC-chemokine stromal cell-derived factor-1 (SDF-1) is a highly efficacious lymphocyte chemoattractant. Chemokines act on responsive leukocyte subsets through G-protein-coupled seven-transmembrane receptors, which are also used by distinct strains of HIV-1 as cofactors for viral entry. Laboratory-adapted and some T-cell-line-tropic (T-tropic) primary viruses use the orphan chemokine receptor LESTR/fusin (also known as fusin), whereas macrophage-tropic primary HIV-1 isolates use CCR-5 and CCR-3 (refs 7-11), which are receptors for known CC chemokines. Testing of potential receptors demonstrated that SDF-1 signalled through, and hence 'adopted', the orphan receptor LESTR, which we therefore designate CXC-chemokine receptor-4 (CXCR-4). SDF-1 induced an increase in intracellular free Ca2+ and chemotaxis in CXCR-4-transfected cells. Because SDF-1 is a biological ligand for the HIV-1 entry cofactor LESTR, we tested whether it inhibited HIV-1. SDF-1 inhibited infection by T-tropic HIV-1 of HeLa-CD4 cells, CXCR-4 transfectants, and peripheral blood mononuclear cells (PBMCs), but did not affect CCR-5-mediated infection by macrophage-tropic (M-tropic) and dual-tropic primary HIV-1.
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The Center for Blood Research, Dana-Farber Cancer Institute, Boston, Massachusetts 02115, USA.
Farzan
M
M
Choe
H
H
Parolin
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C
Clark-Lewis
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I
Sodroski
J
J
Springer
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D000818:Animals; D019380:Anti-HIV Agents / Q000138:chemical synthesis / Q000378:metabolism / Q000494:pharmacology*; D016466:CHO Cells; D002118:Calcium / Q000378:metabolism; D002460:Cell Line; D054377:Chemokine CXCL12; D018925:Chemokines / Q000138:chemical synthesis / Q000235:genetics / Q000378:metabolism* / Q000494:pharmacology*; D019743:Chemokines, CXC; D002633:Chemotaxis; D006224:Cricetinae; D004285:Dogs; D015497:HIV-1 / Q000187:drug effects* / Q000378:metabolism; D006367:HeLa Cells; D006801:Humans; D007963:Leukocytes, Mononuclear / Q000821:virology; D008024:Ligands; D008264:Macrophages / Q000821:virology; D008561:Membrane Fusion; D008565:Membrane Proteins / Q000378:metabolism*; D051379:Mice; D019718:Receptors, CXCR4; D015728:Receptors, HIV / Q000378:metabolism*; D014162:Transfection
D019380:Anti-HIV Agents; C515255:CXCL12 protein, human; D054377:Chemokine CXCL12; D018925:Chemokines; D019743:Chemokines, CXC; C515256:Cxcl12 protein, mouse; D008024:Ligands; D008565:Membrane Proteins; D019718:Receptors, CXCR4; D015728:Receptors, HIV; D002118:Calcium