Defining Criteria for Oligomannose Immunogens for HIV Using Icosahedral Virus Capsid Scaffolds

Abstract

Summary The broadly neutralizing antibody 2G12 recognizes a conserved cluster of high mannose glycans on the surface envelope spike of HIV suggesting that the “glycan shield” defense of the virus can be breached and may, under the right circumstances, serve as a vaccine target. In an attempt to recreate features of the glycan shield semi-synthetically, oligomannosides were coupled to surface lysines on the icosahedral capsids of bacteriophage Qβ and cowpea mosaic virus (CPMV). The Qβ glycoconjugates, but not CPMV, presented oligomannose clusters that bind the antibody 2G12 with high affinity. However, Abs against these 2G12 epitopes were not detected in immunized rabbits. Rather, alternative oligomannose epitopes on the conjugates were immunodominant and elicited high titres of anti-mannose Abs that do not cross-react with the HIV envelope. The results presented reveal important design considerations for a carbohydrate-based vaccine component for HIV.

Glycodendrimers and Their Derivatives as Potential Therapeutic Agents

“…In this approach, first and second generation glycodendrons have been prepared, which were conveniently functionalized for further conjugation on different scaffolds including a fullerene molecule or a virus-like particle protein. [32,33] …”

“…The inhibition data based on the number of carbohydrates radiuses showed that, in each case, the average affinity of a single glycoside of the fullerenes towards WaaC was significantly enhanced when it displayed as a multimer, thus demonstrating an multivalent effect. [21] Multivalent glycoconjugates are also used in anti adhesion leukacytotes to the endothelium for the prevention of inflammation.…”

Developing strategies to enhance and focus humoral immune responses using filamentous phage as a model antigen

“…Several recent studies have used viruses and virus-like particles as immunogenic scaffolds for a variety of molecules including glycans. [38][39][40][41] The requirements for viral self-assembly of rigidity and symmetry result in regular spacing of fixed, chemically accessible groups, thus making these platforms ideal for multivalent attachment of oligosaccharide determinants. Oligosaccharide cluster density is increasingly recognized as a major determinant for immunological discrimination between self and non-self CHO antigens.…”

“…Possible reasons for these failures include inadequate clustering of glycans, conformational flexibility induced by linker moieties and immunodominance of irrelevant CHO epitopes. 38 In collaboration with D. Bundle and J.J. Bailey (University of Alberta), we are pursuing an alternate strategy in which short chain oligosaccharides (mono-, di-, tetra-and/or pentamannose) will be attached to the filamentous phage pVIII via very short heterobifunctional linkers so as to minimize conformational flexibility (Fig. 5).…”

“…45,46 It has recently been shown that the glycans of the native HIV-1 gp120 trimer consist almost entirely of unprocessed Man 5-9 GlcNAc 2 rather than complex-type gycans, thus exposing dense clusters of terminal mannose residues to the immune system. 47 Several multivalent oligomannose antigens have been designed to mimic this structure using various platforms, including the icosahedral viruses cowpea mosaic virus and Q β phage, 38 but all have failed to elicit 2G12-like Abs that cross-react with high-mannose glycans on gp120 and neutralize HIV-1. Possible reasons for these failures include inadequate clustering of glycans, conformational flexibility induced by linker moieties and immunodominance of irrelevant CHO epitopes.…”