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 migr ation of leukocytes(1,2). There are two subfamilies, the CXC and the C C chemokines, We recently found that the CXC-chemokine stromal cell-de rived factor-1 (SDF-1)(3,4) is a highly efficacious lymphocyte chemoat tractant(5). 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-ad apted and some T-cell-line-tropic (T-tropic) primary viruses use the o rphan chemokine receptor LESTR/fusin (also known as fusin)(6-8), where as macrophage-tropic primary HIV-1 isolates use CCR-5 and CCR-3 (refs 7-11), which are receptors for known CC chemokines, Testing of potenti al receptors demonstrated that SDF-1 signalled through, and hence 'ado pted', the orphan receptor LESTR, which we therefore designate CXC-che mokine receptor-4 (CXCR-4). SDF-1 induced an increase in intracellular free Ca2+ and chemotaxis in CXCR-4-transfected cells. Because SDF-1 i s a biological ligand for the HIV-1 entry cofactor LESTR, we tested wh ether it inhibited HIV-1, SDF-1 inhibited infection by T-tropic HIV-1 of HeLa-CD4 cells, CXCR-4 transfectants, and peripheral blood mononucl ear cells (PBMCs), but did not affect CCR-5-mediated infection by macr ophage-tropic (M-tropic) and dual-tropic primary HIV-1.