Hitting the sweet spot on HIV: Immunological perspectives on synthetic carbohydrate vaccine strategies

The broadly neutralizing Ab 2G12 recognizes a conserved cluster of high mannose (e.g. GlcNAc2Man9) on the glycan shield of HIV-1 gp120. Hence, this shield, normally considered as defensive armour against humoral immunity, may be a potential vaccine target. Synthetic oligomannosides containing the D1 and/or D3 arm motifs (e.g. Man4 and Man 9) of high mannose were identified as potential building blocks for vaccine immunogens based on their ability to bind 2G12 as effectively as GlcNAc 2Man9. An initial study of Man4, the minimal recognition motif for 2G12, conjugated to BSA emphasized the importance of multivalency for 2G12 recognition. Furthermore, immunization with BSA-(Man4) 14 showed that Abs can be raised against the Man4. However, these Abs did not cross-react with gp120.;Improved Man4-and Man9-based mimics of the clustered oligomannose on gp120 may enhance the chances of generating 2G12-like specificities. Icosahedral virus capsids, like Qbeta, wherein the geometry of conjugation residues enables glycan clustering, proved to be effective scaffolds for creating high affinity epitopes for 2G12. Strong IgG titers were elicited by QbetaK16M-Man 4 and QbetaK16M-Man9 that recognized related synthetic oligomannosides, but not the high mannose glycans which cover gp120. Man 9 termini-specific IgG were detected in some immune sera which suggests that differences in structural presentation/conformation may exist between these two types of related glycans (i.e. Man8/9 and GlcNAc 2Man8/9) that enable the immunological discrimination observed. Furthermore, the elicited Abs bound to glycan epitopes other than the high affinity epitopes for 2G12 on Qbeta glycoconjugates. A population of poorly clustered glycans on these conjugates may contribute to the generation of Abs incompatible with gp120.;A dendron display strategy was investigated to create a homogenous array of oligomannose that mimics the overall density and rigidity of oligomannose on gp120. The prevalence of high affinity epitopes for 2G12 on BSA-glycodendrons was similar to that described for the best Qbeta conjugates despite significantly reduced multivalency on BSA-glycodendrons. Moreover, these glycodendrons were nearly homogenous as far as glycan loading. The BSA-glycodendrons generally elicited similar anti-mannose Ab specificities as described above, including Man9 termini-specific Abs, but these Abs did not cross-react with gp120.;Key factors pertaining to antigenic and immunogenic mimicry of the glycan shield have been elucidated and addressed; however, further design refinements are needed to direct anti-mannose Ab responses towards gp120-reactive specificities.