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: Juan J Garcia-Vallejo, Nathalie Koning, Martino Ambrosini, Hakan Kalay, Ilona Vuist, Ramin Sarrami-Forooshani, Teunis B H Geijtenbeek, Yvette van Kooyk
• Journal: International immunology (Int Immunol) Vol. 25 Issue 4 Pg. 221-33 (Apr 2013) ISSN: 1460-2377 [Electronic] England
• PMID: 23291968 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• Cell Adhesion Molecules
• DC-specific ICAM-3 grabbing nonintegrin
• Dendrimers
• HIV Envelope Protein gp120
• Lectins, C-Type
• Lewis Blood Group Antigens
• Polysaccharides
• Receptors, Cell Surface

Topics

• Binding, Competitive
• Cell Adhesion Molecules (agonists, immunology)
• Cell Differentiation (drug effects)
• Cells, Cultured
• Dendrimers (chemistry)
• Dendritic Cells (drug effects, immunology, virology)
• HIV Envelope Protein gp120 (metabolism)
• HIV Infections (prevention & control, transmission)
• HIV-1 (immunology)
• Humans
• Immune Evasion
• Lectins, C-Type (agonists, immunology)
• Lewis Blood Group Antigens (chemistry)
• Molecular Targeted Therapy
• Polysaccharides (agonists, chemical synthesis, pharmacology)
• Receptors, Cell Surface (agonists, immunology)
• Structure-Activity Relationship
• Virus Internalization (drug effects)