title: Glycodendrimers prevent HIV transmission via DC-SIGN on dendritic cells.
abstract: Dendritic cells (DCs) are antigen-presenting cells efficient in capturing pathogens, and processing their antigenic determinants for presentation to antigen-specific T cells to induce robust immune responses. Their location at peripheral tissues and the expression of pattern-recognition receptors, among them DC-specific intercellular adhesion molecule-3-grabbing non-integrin (DC-SIGN), facilitates the capture of pathogens before spreading. However, some pathogens have developed strategies to escape the immune system. One of the most successful is HIV-1, which targets DC-SIGN for transport to the lymph node where the virus infects CD4(+) T cells. Contact of HIV-1 with DC-SIGN is thus the first event in the pathogenic cascade and, therefore, it is the primary target point for therapies aimed at HIV infection prevention. DC-SIGN recognizes specific glycans on HIV-1 and this interaction can be blocked by competitive inhibition through glycans. Although the affinity of glycans is relatively low, multivalency may increase avidity and the strength to compete with HIV-1 virions. We have designed multivalent dendrimeric compounds based on Lewis-type antigens that bind DC-SIGN with high selectivity and avidity and that effectively block gp120 binding to DC-SIGN and, consequently, HIV transmission to CD4(+) T cells. Binding to DC-SIGN and gp120 inhibition was higher on glycodendrimers with larger molecular diameter, indicating that the geometry of the compounds is an important factor determining their functionality. Our compounds elicited DC-SIGN internalization, a property of the receptor upon triggering, but did not affect the maturation status of DCs. Thus, Le(X) glycodendrimers could be incorporated into topic prophylactic approaches for the prevention of HIV-1 transmission.
authors.affiliation: Department of Molecular Cell Biology and Immunology, VU University Medical Center, Amsterdam, The Netherlands.
authors.forename: Juan J
authors.initials: JJ
authors.lastname: Garcia-Vallejo
authors.forename: Nathalie
authors.initials: N
authors.lastname: Koning
authors.forename: Martino
authors.initials: M
authors.lastname: Ambrosini
authors.forename: Hakan
authors.initials: H
authors.lastname: Kalay
authors.forename: Ilona
authors.initials: I
authors.lastname: Vuist
authors.forename: Ramin
authors.initials: R
authors.lastname: Sarrami-Forooshani
authors.forename: Teunis B H
authors.initials: TB
authors.lastname: Geijtenbeek
authors.forename: Yvette
authors.initials: Y
authors.lastname: van Kooyk
mesh_terms: D001667:Binding, Competitive; D015815:Cell Adhesion Molecules / Q000819:agonists / Q000276:immunology*; D002454:Cell Differentiation / Q000187:drug effects; D002478:Cells, Cultured; D050091:Dendrimers / Q000737:chemistry*; D003713:Dendritic Cells / Q000187:drug effects / Q000276:immunology* / Q000821:virology; D015699:HIV Envelope Protein gp120 / Q000378:metabolism; D015658:HIV Infections / Q000517:prevention & control* / Q000635:transmission*; D015497:HIV-1 / Q000276:immunology*; D006801:Humans; D057131:Immune Evasion; D037181:Lectins, C-Type / Q000819:agonists / Q000276:immunology*; D007983:Lewis Blood Group Antigens / Q000737:chemistry*; D058990:Molecular Targeted Therapy; D011134:Polysaccharides / Q000819:agonists / Q000138:chemical synthesis / Q000494:pharmacology*; D011956:Receptors, Cell Surface / Q000819:agonists / Q000276:immunology*; D013329:Structure-Activity Relationship; D053586:Virus Internalization / Q000187:drug effects; D000099215:DC-Specific ICAM-3 Grabbing Nonintegrin
chemical_list: D015815:Cell Adhesion Molecules; D050091:Dendrimers; D015699:HIV Envelope Protein gp120; D037181:Lectins, C-Type; D007983:Lewis Blood Group Antigens; D011134:Polysaccharides; D011956:Receptors, Cell Surface; D000099215:DC-Specific ICAM-3 Grabbing Nonintegrin