The Lymphocyte Chemoattractant SDF-1 Is a Ligand for LESTR/fusin and Blocks HIV-1 Entry

Nature. 1996 Aug 29;382(6594):829-33. doi: 10.1038/382829a0.

Abstract

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.

Publication types

  • Research Support, Non-U.S. Gov't
  • Research Support, U.S. Gov't, P.H.S.

MeSH terms

  • Animals
  • Anti-HIV Agents / chemical synthesis
  • Anti-HIV Agents / metabolism
  • Anti-HIV Agents / pharmacology*
  • CHO Cells
  • Calcium / metabolism
  • Cell Line
  • Chemokine CXCL12
  • Chemokines / chemical synthesis
  • Chemokines / genetics
  • Chemokines / metabolism*
  • Chemokines / pharmacology*
  • Chemokines, CXC*
  • Chemotaxis
  • Cricetinae
  • Dogs
  • HIV-1 / drug effects*
  • HIV-1 / metabolism
  • HeLa Cells
  • Humans
  • Leukocytes, Mononuclear / virology
  • Ligands
  • Macrophages / virology
  • Membrane Fusion
  • Membrane Proteins / metabolism*
  • Mice
  • Receptors, CXCR4
  • Receptors, HIV / metabolism*
  • Transfection

Substances

  • Anti-HIV Agents
  • CXCL12 protein, human
  • Chemokine CXCL12
  • Chemokines
  • Chemokines, CXC
  • Cxcl12 protein, mouse
  • Ligands
  • Membrane Proteins
  • Receptors, CXCR4
  • Receptors, HIV
  • Calcium