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Journal of Virology, April 2005, p. 4589-4598, Vol. 79, No. 8
0022-538X/05/$08.00+0     doi:10.1128/JVI.79.8.4589-4598.2005
Copyright © 2005, American Society for Microbiology. All Rights Reserved.

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

Greg A. Snyder,1 Jennifer Ford,1 Parizad Torabi-Parizi,2 James A. Arthos,3 Peter Schuck,4 Marco Colonna,5 and Peter D. Sun1*

Laboratory of Immunogenetics, Structural Immunology Section, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Rockville,1 Laboratory of Immunoregulation, National Institute of Allergy and Infectious Diseases,3 Division of Bioengineering & Physical Science, Office of Research Services, Office of the Director, National Institutes of Health, Bethesda, Maryland,4 Department of Medicine, Emory University, Atlanta, Georgia,2 Department of Pathology and Immunology, Washington University School of Medicine, St. Louis, Missouri5

Received 26 November 2003/ Accepted 23 November 2004

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, Fc{gamma}RIIb and Fc{gamma}RIII, 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.

* Corresponding author. Mailing address: Laboratory of Immunogenetics, Structural Immunology Section, NIAID, NIH, Twinbrook II, 12441 Parklawn Dr., Rockville, MD 20852. Phone: (301) 496-3792. Fax: (301) 402-0284. E-mail: psun{at}nih.gov.

Journal of Virology, April 2005, p. 4589-4598, Vol. 79, No. 8
0022-538X/05/$08.00+0     doi:10.1128/JVI.79.8.4589-4598.2005
Copyright © 2005, American Society for Microbiology. All Rights Reserved.



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