Binding of ALX40-4C to APJ, a CNS-based receptor, inhibits its utilization as a co-receptor by HIV-1

Virology. 2003 Jul 20;312(1):196-203. doi: 10.1016/s0042-6822(03)00185-5.


APJ, a G protein-coupled seven-transmembrane receptor, has been shown to serve as a co-receptor for the entry of human immunodeficiency virus type 1 (HIV-1), and it is dramatically expressed in central nervous system (CNS)-based cells. ALX40-4C was identified as a small-molecule antagonist of the chemokine receptor CXCR4, which can specifically inhibit HIV-1 entry via this co-receptor. In this study, we demonstrated that ALX40-4C inhibited both APJ- and CXCR4/APJ-mediated cell membrane fusion in a dose-dependent manner. In competitive binding assays, (125)I-Apelin13 was replaced by ALX40-4C with an IC(50) of 2.9 microM, as compared with an IC(50) of 0.2 nM for Apelin13. Furthermore, ALX40-4C could block ligand-induced APJ internalization and signaling. ALX40-4C, as an antagonist to APJ, directly binds to and prevents use of APJ as a HIV-1 co-receptor. Thus, ALX-4C has potential utility for further elucidation of HIV-1 neuropathogenesis and therapy of HIV-1-induced encephalopathy.

Publication types

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

MeSH terms

  • Apelin Receptors
  • Binding, Competitive / drug effects
  • Cell Line
  • Cell Membrane / drug effects
  • Cell Membrane / metabolism
  • Central Nervous System / metabolism*
  • Dopamine D2 Receptor Antagonists*
  • Dose-Response Relationship, Immunologic
  • HIV Envelope Protein gp120 / metabolism
  • HIV-1 / metabolism*
  • Humans
  • Membrane Fusion / drug effects
  • Oligopeptides / metabolism
  • Oligopeptides / pharmacology*
  • Protein Binding / drug effects
  • Receptors, CXCR4 / metabolism
  • Receptors, Dopamine D2 / metabolism*
  • Receptors, G-Protein-Coupled*


  • APLNR protein, human
  • Apelin Receptors
  • Dopamine D2 Receptor Antagonists
  • HIV Envelope Protein gp120
  • N-alpha-acetyl-nona-D-arginine amide acetate
  • Oligopeptides
  • Receptors, CXCR4
  • Receptors, Dopamine D2
  • Receptors, G-Protein-Coupled