Identification of the B cell superantigen-binding site of HIV-1 gp120.
Previous studies showed that the gp120 envelope protein of HIV-1 is able to crosslink membrane IgM on normal human B cells and to induce their activation in a V(H)3 immunoglobulin gene-family-specific manner. Because this V(H) gene family is the largest in the human repertoire, this superantigen (SAg) property is thought to have deleterious consequences for the host, including a progressive decline of B cells with progression of the HIV-1-induced disease. Here, we have identified the sequence motifs on gp120 involved in SAg binding to normal Igs. We show that this SAg-binding activity is present in gp120s from highly divergent isolates of HIV-1 belonging to clades derived from various geographical origins, and that carbohydrate residues are not essential for its 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 C4 constant domain. The most critical residues appear to be Leu395-Asp397 and Ile425-Gln427. Residues from the C2 constant 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.
Karray
S
S
Departement d'Immunologie, Institut Pasteur, Paris, France.
Zouali
M
M
D000595:Amino Acid Sequence; D001402:B-Lymphocytes / Q000276:immunology*; D004252:DNA Mutational Analysis; D000939:Epitopes / Q000276:immunology; D005803:Genes, Immunoglobulin; D015699:HIV Envelope Protein gp120 / Q000235:genetics* / Q000276:immunology*; D015497:HIV-1 / Q000145:classification / Q000276:immunology*; D006801:Humans; D007073:Immunoglobulin E / Q000235:genetics; D007075:Immunoglobulin M / Q000235:genetics; D008969:Molecular Sequence Data; D009842:Oligopeptides / Q000494:pharmacology; D011485:Protein Binding / Q000187:drug effects; D011994:Recombinant Proteins / Q000276:immunology; D017386:Sequence Homology, Amino Acid; D018089:Superantigens / Q000276:immunology*
D000939:Epitopes; D015699:HIV Envelope Protein gp120; D007075:Immunoglobulin M; D009842:Oligopeptides; D011994:Recombinant Proteins; D018089:Superantigens; D007073:Immunoglobulin E