A tyrosine-sulfated peptide based on the N terminus of CCR5 interacts witha CD4-enhanced epitope of the HIV-1 gp120 envelope glycoprotein and inhibits HIV-1 entry

The sequential association of the human immunodeficiency virus type 1 (HIV- 1) envelope glycoprotein gp120 with CD4 and a seven-transmembrane segment c oreceptor such as CC RB or CXCR4 initiates entry of the virus into its targ et cell. The N terminus of CCR5, which contains several sulfated tyrosines, plays a critical role in the CD4-dependent association of gp120 with CCR5 and in viral entry. Here we demonstrate that a tyrosine-sulfated peptide ba sed on the N terminus of CCR5, but not its unsulfated analogue, inhibits in fection of macrophages and peripheral blood mononuclear cells by CCR5-depen dent, but not CXCR4-dependent, HIV-1 isolates. The sulfated peptide also in hibited the association of CCR5-expressing cells with gp120-soluble CD4 com plexes and, less efficiently, with MIP-1 alpha. Moreover, this peptide inhi bited the precipitation of gp120 by 48d and 23e antibodies, which recognize CD4-inducible gp120 epitopes, but not by several other antibodies that rec ognize proximal epitopes, The ability of the sulfated peptide to block 48d association with gp120 was dependent in part on seven tropism-determining r esidues in the third variable (V3) and fourth conserved (C4) domains of gp1 20, These data underscore the important role of the N-terminal sulfate moie ties of CCR5 in the entry of R5 HIV-1 isolates and Localize a critical cont act between gp120 and CCR5.