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

Abstract

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 IC 50 in the nanomolar range. A second-generation Man 9 dendron was identified as a potential immunogen for HIV vaccine development and as a potential antiviral agent.glycodendron ͉ high mannose ͉ multivalency ͉ HIV vaccine ͉ antiviral agent

Envelope glycans of immunodeficiency virions are almost entirely oligomannose antigens

“…The identification of its epitope as a cluster of Manα1→2Man termini within the intrinsic mannose patch of gp120 (17) has encouraged the development of vaccines based around biological (19,27,(31)(32)(33) and synthetic Manα1→2Man clusters (34)(35)(36)(37)(38). A major limitation of any vaccine based on 2G12 recognition is the absence of its cognate epitope on the epidemiologically important clade C. The specific Asn residues required for 2G12 neutralization are absent in clade C isolates, explaining their resistance to 2G12.…”

An oligosaccharide-based HIV-1 2G12 mimotope vaccine induces carbohydrate-specific antibodies that fail to neutralize HIV-1 virions

“…Surface plasmon resonance studies of 2G12 binding to this construct yielded results nearly identical to ours in that the effect of clustering on enhanced antibody recognition was clearly evident. Similarly, synthetic multivalent dendrons presenting Man 4 or Man 9 oligosaccharides were shown to induce good binding of 2G12 and have been proposed as potential vaccine components (35). Although such approaches to ''direct'' the immune response to more relevant antibody generation are important, a successful strategy will likely need to encompass a method to ''lock'' the optimal oligosaccharide conformation in a preferred orientation.…”

Carbohydrate-based vaccines with a glycolipid adjuvant for breast cancer

“…A multivalent glycan vaccine or carbohydrate conjugated with a carrier protein and administered with an immunological adjuvant has been adopted to increase the immunogenicity of carbohydrates. As an example, a GH vaccine with ∼700 GH units conjugated to one keyhole limpet hemocyanin (KLH) protein was prepared and administered together with a mixture of saponins called QS21 adjuvant (18,(22)(23)(24)(25), and it had been shown that treatment of mice with GH-KLH/QS21 could induce antisera against GH-positive cell lines without autoimmune reactions (14,23). Furthermore, the vaccine was fairly well-tolerated in a phase I clinical trial for metastatic breast cancer patients.…”