IDENTIFICATION OF THE B-CELL SUPERANTIGEN-BINDING SITE OF HIV-1 GP120

Previous studies showed that the gp120 envelope protein of HIV-1 is ab le to crosslink membrane IgM on normal human B cells and to induce the ir activation in a V(H)3 immunoglobulin gene-family-specific manner. B ecause this V-H gene family is the largest in the human repertoire, th is superantigen (SAg) property is thought to have deleterious conseque nces for the host, including a progressive decline of B cells with pro gression of the HIV-1-induced disease, Here, we have identified the se quence motifs on gp120 involved in SAg binding to normal Igs, We show that this SAg-binding activity is present in gp120s from highly diverg ent isolates of HIV-1 belonging to clades derived from various geograp hical origins, and that carbohydrate residues are not essential for it s expression. The SAg-binding site is formed by protein sequences from two regions of the gp120 molecule, The core motif is a discontinuous epitope spanning the V4 variable domain and the amino-terminal region flanking the C2 constant domain, The most critical residues appear to be Leu(395)-Asp(397) and Ile(425)-Gln(427), Residues from the C2 const ant domain (positions 252-272) also seem to play an accessory role in SAg binding of gp120 to normal human Igs, These findings are important in the design of a successful gp120-based vaccine against HIV-1.