A Highly Conserved Arginine in gp120 Governs HIV-1 Binding to Both Syndecans and CCR5 via Sulfated Motifs

• Published in: The Journal of biological chemistry Vol. 280; no. 47; pp. 39493 - 39504
• Main Authors: de Parseval, Aymeric, Bobardt, Michael D., Chatterji, Anju, Chatterji, Udayan, Elder, John H., David, Guido, Zolla-Pazner, Susan, Farzan, Michael, Lee, Tun-Hou, Gallay, Philippe A.
• Format: Journal Article
• Language: English
• Published: United States Elsevier Inc 25.11.2005; American Society for Biochemistry and Molecular Biology
• Subjects: Amino Acid Motifs; Amino Acid Sequence; Amino Acid Substitution; Arginine - chemistry; Binding Sites; Cell Line; Conserved Sequence; HIV Envelope Protein gp120 - chemistry; HIV Envelope Protein gp120 - genetics; HIV Envelope Protein gp120 - metabolism; HIV-1 - genetics; HIV-1 - metabolism; HIV-1 - pathogenicity; Human immunodeficiency virus 1; Humans; Membrane Glycoproteins - chemistry; Membrane Glycoproteins - genetics; Membrane Glycoproteins - metabolism; Models, Biological; Molecular Mimicry; Molecular Sequence Data; Peptide Fragments - chemistry; Peptide Fragments - genetics; Peptide Fragments - metabolism; Proteoglycans - chemistry; Proteoglycans - genetics; Proteoglycans - metabolism; Receptors, CCR5 - chemistry; Receptors, CCR5 - genetics; Receptors, CCR5 - metabolism; Recombinant Fusion Proteins - chemistry; Recombinant Fusion Proteins - genetics; Recombinant Fusion Proteins - metabolism; Sulfates - chemistry; Syndecans
• ISSN: 0021-9258; 1083-351X
• DOI: 10.1074/jbc.M504233200

HIV-1 has maximized its utilization of syndecans. It uses them as in cis receptors to infect macrophages and as in trans receptors to infect T-lymphocytes. In this study, we investigated at a molecular level the mechanisms that control HIV-1-syndecan interactions. We found that a single conserved arginine (Arg-298) in the V3 region of gp120 governs HIV-1 binding to syndecans. We found that an amine group on the side chain of this residue is necessary for syndecan utilization by HIV-1. Furthermore, we showed that HIV-1 binds syndecans via a 6-O sulfation, demonstrating that this binding is not the result of random interactions between basic residues and negative charges, but the result of specific contacts between gp120 and a well defined sulfation in syndecans. Surprisingly, we found that Arg-298, which mediates HIV-1 binding to syndecans, also mediates HIV-1 binding to CCR5. We postulated that HIV-1 recognizes similar motifs on syndecans and CCR5. Supporting this hypothesis, we obtained several lines of evidence that suggest that the 6-O sulfation recognized by HIV-1 on syndecans mimics the sulfated tyrosines recognized by HIV-1 in the N terminus of CCR5. Our finding that CCR5 and syndecans are exploited by HIV-1 via a single determinant echoes the mechanisms by which chemokines utilize these two disparate receptors and suggests that the gp120/chemokine mimicry may represent a common strategy in microbial pathogenesis.