Fab-dimerized glycan-reactive antibodies are a structural category of natural antibodies

Natural antibodies (Abs) can target host glycans on the surface of pathogens. We studied the evolution of glycan-reactive B cells of rhesus macaques and humans using glycosylated HIV-1 envelope (Env) as a model antigen. 2G12 is a broadly neutralizing Ab (bnAb) that targets a conserved glycan patch on Env of geographically diverse HIV-1 strains using a unique heavy-chain (VH) domain-swapped architecture that results in fragment antigen-binding (Fab) dimerization. Here, we describe HIV-1 Env Fab-dimerized glycan (FDG)-reactive bnAbs without VH-swapped domains from simian-human immunodeficiency virus (SHIV)-infected macaques. FDG Abs also recognized cell-surface glycans on diverse pathogens, including yeast and severe acute respiratory syndrome coronavirus 2 (SARS-CoV- 2) spike. FDG precursors were expanded by glycan-bearing immunogens in macaques and were abundant in HIV-1-naive humans. Moreover, FDG precursors were predominately mutated IgM(+) IgD(+)CD27(+), thus suggesting that they originated from a pool of antigen-experienced IgM(+) or marginal zone B cells.

Automated summary

This study highlights the evolution and characteristics of glycan-reactive B cells targeting pathogens in rhesus macaques and humans, particularly focusing on the production of FDG Abs from SHIV-infected macaques without VH-swapped domains. The findings suggest a potential source of glycan-reactive B cells in HIV-1-naive humans, indicating the importance of understanding the immune response to glycans in diverse pathogens.