Identification of Different Binding Sites in the Dendritic Cell-specific Receptor DC-SIGN for Intercellular Adhesion Molecule 3 and HIV-1

• Published in: The Journal of biological chemistry 2002-03, Vol.277 (13), p.11314-11320
• Main Authors: Geijtenbeek, Teunis B.H., van Duijnhoven, Gerard C.F., van Vliet, Sandra J., Krieger, Elmar, Vriend, Gert, Figdor, Carl G., van Kooyk, Yvette
• Format: Article
• Language: English
• Subjects: Amino Acid Sequence; Antigens, CD; Antigens, Differentiation; Binding Sites; Cell Adhesion Molecules - metabolism; DC-SIGN protein; glycoprotein gp120; Glycosylation; HIV-1 - metabolism; Human immunodeficiency virus 1; Humans; intercellular adhesion molecule 3; Lectins - chemistry; Lectins - genetics; Lectins - metabolism; Lectins, C-Type; Models, Molecular; Molecular Sequence Data; Mutagenesis, Site-Directed; Receptors, Cell Surface - chemistry; Receptors, Cell Surface - genetics; Receptors, Cell Surface - metabolism; Sequence Homology, Amino Acid
• ISSN: 0021-9258; 1083-351X
• DOI: 10.1074/jbc.M111532200

The novel dendritic cell (DC)-specific human immunodeficiency virus type 1 (HIV-1) receptor DC-SIGN plays a key role in the dissemination of HIV-1 by DC. DC-SIGN is thought to capture HIV-1 at mucosal sites of entry, facilitating transport to lymphoid tissues, where DC-SIGN efficiently transmits HIV-1 to T cells. DC-SIGN is also important in the initiation of immune responses by regulating DC-T cell interactions through intercellular adhesion molecule 3 (ICAM-3). We have characterized the mechanism of ligand binding by DC-SIGN and identified the crucial amino acids involved in this process. Strikingly, the HIV-1 gp120 binding site in DC-SIGN is different from that of ICAM-3, consistent with the observation that glycosylation of gp120, in contrast to ICAM-3, is not crucial to the interaction with DC-SIGN. A specific mutation in DC-SIGN abrogated ICAM-3 binding, whereas the HIV-1 gp120 interaction was unaffected. This DC-SIGN mutant captured HIV-1 and infected T cells in trans as efficiently as wild-type DC-SIGN, demonstrating that ICAM-3 binding is not necessary for HIV-1 transmission. This study provides a basis for the design of drugs that inhibit or alter interactions of DC-SIGN with gp120 but not with ICAM-3 or vice versa and that have a therapeutic value in immunological diseases and/or HIV-1 infections.