Targeting the carbohydrates on HIV-1: Interaction of oligomannose dendrons with human monoclonal antibody 2G12 and DC-SIGN

• Published in: Proceedings of the National Academy of Sciences - PNAS Vol. 105; no. 10; pp. 3690 - 3695
• Main Authors: Wang, Sheng-Kai, Liang, Pi-Hui, Astronomo, Rena D, Hsu, Tsui-Ling, Hsieh, Shie-Liang, Burton, Dennis R, Wong, Chi-Huey
• Format: Journal Article
• Language: English
• Published: United States National Academy of Sciences 11.03.2008; National Acad Sciences
• Subjects: Antibodies; Antibodies, Monoclonal - metabolism; Antiviral agents; Antivirals; Biochemistry; Biological Sciences; Carbohydrate Metabolism; Carbohydrates; CD4-positive T-lymphocytes; Cell Adhesion Molecules - metabolism; Dendrimers; Dendrimers - chemical synthesis; Dendrimers - chemistry; Dendrimers - metabolism; dendritic cells; epitopes; Flow Cytometry; Glycoproteins; Glycosylation; HIV; HIV 1; HIV-1 - metabolism; Human immunodeficiency virus; Human immunodeficiency virus 1; Humans; Immune system; Infections; Inhibitory concentration 50; Jurkat Cells; lectins; Lectins, C-Type - metabolism; Ligands; Lymph nodes; Mannose - chemical synthesis; Mannose - chemistry; Mannose - metabolism; microarray technology; monoclonal antibodies; Physical Sciences; Polymers - chemistry; Polymers - metabolism; Polysaccharides; Receptors, Cell Surface - metabolism; Spectrometry, Mass, Matrix-Assisted Laser Desorption-Ionization; T cell receptors; T lymphocytes; Vaccination; vaccine development; Vaccines; viruses
• ISSN: 0027-8424; 1091-6490; 1091-6490
• DOI: 10.1073/pnas.0712326105

It is widely accepted that the heavily glycosylated glycoprotein gp120 on the surface of HIV-1 shields peptide epitopes from recognition by the immune system and may promote infection in vivo by interaction with dendritic cells and transport to tissue rich in CD4⁺ T cells such as lymph nodes. A conserved cluster of oligomannose glycans on gp120 has been identified as the epitope recognized by the broadly HIV-1-neutralizing monoclonal antibody 2G12. Oligomannose glycans are also the ligands for DC-SIGN, a C-type lectin found on the surface of dendritic cells. Multivalency is fundamental for carbohydrate-protein interactions, and mimicking of the high glycan density on the virus surface has become essential for designing carbohydrate-based HIV vaccines and antiviral agents. We report an efficient synthesis of oligomannose dendrons, which display multivalent oligomannoses in high density, and characterize their interaction with 2G12 and DC-SIGN by a glycan microarray binding assay. The solution and the surface binding analysis of 2G12 to a prototype oligomannose dendron clearly demonstrated the efficacy of dendrimeric display. We further showed that these glycodendrons inhibit the binding of gp120 to 2G12 and recombinant dimeric DC-SIGN with IC₅₀ in the nanomolar range. A second-generation Man₉ dendron was identified as a potential immunogen for HIV vaccine development and as a potential antiviral agent.