Total Syntheses of Tumor-Related Antigens N3: Probing the Feasibility Limits of the Glycal Assembly Method

The total syntheses of two octasaccharide antigens isolated from human milk, 1 and 2, and their corresponding allyl glycosides, 3 and 4, have been achieved by utilizing the glycal method. Convergent assembly of the core hexasaccharides and concurrent introduction of two α-l-fucosyl moieties at the late stage of the syntheses provided these complex carbohydrates in a concise manner. With synthetic material obtained, biological evaluations of these antigens as potential gastrointestinal cancer immunotherapeutic agents have been initiated

Staged induction of HIV-1 glycan–dependent broadly neutralizing antibodies

A preventive HIV-1 vaccine should induce HIV-1–specific broadly neutralizing antibodies (bnAbs). However, bnAbs generally require high levels of somatic hypermutation (SHM) to acquire breadth, and current vaccine strategies have not been successful in inducing bnAbs. Because bnAbs directed against a glycosylated site adjacent to the third variable loop (V3) of the HIV-1 envelope protein require limited SHM, the V3-glycan epitope is an attractive vaccine target. By studying the cooperation among multiple V3-glycan B cell lineages and their coevolution with autologous virus throughout 5 years of infection, we identify key events in the ontogeny of a V3-glycan bnAb. Two autologous neutralizing antibody lineages selected for virus escape mutations and consequently allowed initiation and affinity maturation of a V3-glycan bnAb lineage. The nucleotide substitution required to initiate the bnAb lineage occurred at a low-probability site for activation-induced cytidine deaminase activity. Cooperation of B cell lineages and an improbable mutation critical for bnAb activity defined the necessary events leading to breadth in this V3-glycan bnAb lineage. These findings may, in part, explain why initiation of V3-glycan bnAbs is rare, and suggest an immunization strategy for inducing similar V3-glycan bnAbs