title: Characterization of DC-SIGN/R interaction with human immunodeficiency virus type 1 gp120 and ICAM molecules favors the receptor's role as an antigen-capturing rather than an adhesion receptor.
abstract: The dendritic cell (DC)-specific intercellular adhesion molecule 3 (ICAM-3)-grabbing nonintegrin binding receptor (DC-SIGN) was shown to bind human immunodeficiency virus type 1 (HIV-1) viral envelope protein gp120 and proposed to function as a Trojan horse to enhance trans-virus infection to host T cells. To better understand the mechanism by which DC-SIGN and DC-SIGNR selectively bind HIV-1 gp120, we constructed a series of deletion mutations in the repeat regions of both receptors. Different truncated receptors exist in different oligomeric forms. The carbohydrate binding domain without any repeats was monomeric, whereas the full extracellular receptors existed as tetramers. All reconstituted receptors retained their ability to bind gp120. The dissociation constant, however, differed drastically from micromolar values for the monomeric receptors to nanomolar values for the tetrameric receptors, suggesting that the repeat region of these receptors contributes to the avidity of gp120 binding. Such oligomerization may provide a mechanism for the receptor to selectively recognize pathogens containing multiple high-mannose-concentration carbohydrates. In contrast, the receptors bound to ICAMs with submicromolar affinities that are similar to those of two nonspecific cell surface glycoproteins, FcgammaRIIb and FcgammaRIII, and the oligomerization of DC-SIGNR resulted in no increase in binding affinity to ICAM-3. These findings suggest that DC-SIGN may not discriminate other cell surface glycoproteins from ICAM-3 binding. The pH dependence in DC-SIGN binding to gp120 showed that the receptor retained high-affinity gp120 binding at neutral pH but lost gp120 binding at pH 5, suggesting a release mechanism of HIV in the acidic endosomal compartment by DC-SIGN. Our work contradicts the function of DC-SIGN as a Trojan horse to facilitate HIV-1 infection; rather, it supports the function of DC-SIGN/R (a designation referring to both DC-SIGN and DC-SIGNR) as an antigen-capturing receptor.
authors.affiliation: Laboratory of Immunogenetics, Structural Immunology Section, NIAID, NIH, Twinbrook II, 12441 Parklawn Dr., Rockville, MD 20852, USA.
authors.forename: Greg A
authors.initials: GA
authors.lastname: Snyder
authors.forename: Jennifer
authors.initials: J
authors.lastname: Ford
authors.forename: Parizad
authors.initials: P
authors.lastname: Torabi-Parizi
authors.forename: James A
authors.initials: JA
authors.lastname: Arthos
authors.forename: Peter
authors.initials: P
authors.lastname: Schuck
authors.forename: Marco
authors.initials: M
authors.lastname: Colonna
authors.forename: Peter D
authors.initials: PD
authors.lastname: Sun
mesh_terms: D000818:Animals; D015703:Antigens, CD / Q000276:immunology*; D015815:Cell Adhesion Molecules; D003713:Dendritic Cells / Q000276:immunology*; D015488:HIV Antigens / Q000276:immunology*; D015699:HIV Envelope Protein gp120 / Q000276:immunology*; D037181:Lectins, C-Type / Q000276:immunology*; D051379:Mice; D011956:Receptors, Cell Surface; D015728:Receptors, HIV / Q000276:immunology*; D017384:Sequence Deletion; D000099215:DC-Specific ICAM-3 Grabbing Nonintegrin
chemical_list: D015703:Antigens, CD; D015815:Cell Adhesion Molecules; D015488:HIV Antigens; D015699:HIV Envelope Protein gp120; D037181:Lectins, C-Type; D011956:Receptors, Cell Surface; D015728:Receptors, HIV; D000099215:DC-Specific ICAM-3 Grabbing Nonintegrin; C483616:ICAM3 protein, human