Synthesis and Immunological Evaluation of Pentamannose-Based HIV-1 Vaccine Candidates.

Dense glycosylation and the trimeric conformation of the human immunodeficiency virus-1 (HIV-1) envelope protein limit the accessibility of some cellular glycan processing enzymes and end up with high-mannose-type N -linked glycans on the envelope spike, among which the Man 5 GlcNAc 2 structure occupies a certain proportion. The Man 5 GlcNAc 2 glycan composes the binding sites of some potent broadly neutralizing antibodies, and some lectins that can bind Man 5 GlcNAc 2 show HIV-neutralizing activity. Therefore, Man 5 GlcNAc 2 is a potential target for HIV-1 vaccine development. Herein, a highly convergent and effective strategy was developed for the synthesis of Man 5 and its monofluoro-modified, trifluoro-modified, and S -linked analogues. We coupled these haptens to carrier protein CRM197 and evaluated the immunogenicity of the glycoconjugates in mice. The serological assays showed that the native Man 5 conjugates failed to induce Man 5 -specific antibodies in vivo , while the modified analogue conjugates induced stronger antibody responses. However, these antibodies could not bind the native gp120 antigen. These results demonstrated that the immune tolerance mechanism suppressed the immune responses to Man 5 -related structures and the conformation of glycan epitopes on the synthesized glycoconjugates was distinct from that of native glycan epitopes on gp120.