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.
- Klíčová slova
- FDG Abs, Fab dimerization, HIV-1 Env glycans, IgM-memory B cells, SARS-CoV-2 spike glycans, glycan-dependent Ab binding, marginal zone B cells, natural Abs,
- MeSH
- B-lymfocyty imunologie MeSH
- COVID-19 imunologie MeSH
- dimerizace MeSH
- epitopy imunologie MeSH
- genové produkty env - virus lidské imunodeficience chemie genetika imunologie MeSH
- glykoprotein S, koronavirus imunologie MeSH
- glykosylace MeSH
- HIV infekce imunologie MeSH
- HIV protilátky imunologie MeSH
- HIV-1 imunologie MeSH
- imunoglobuliny - Fab fragmenty chemie imunologie MeSH
- lidé MeSH
- Macaca mulatta MeSH
- neutralizující protilátky imunologie MeSH
- polysacharidy chemie imunologie MeSH
- receptory antigenů B-buněk chemie MeSH
- SARS-CoV-2 imunologie MeSH
- široce neutralizující protilátky imunologie MeSH
- vakcíny imunologie MeSH
- virus opičí imunodeficience genetika imunologie MeSH
- zvířata MeSH
- Check Tag
- lidé MeSH
- zvířata MeSH
- Publikační typ
- časopisecké články MeSH
- práce podpořená grantem MeSH
- Research Support, N.I.H., Extramural MeSH
- Názvy látek
- epitopy MeSH
- genové produkty env - virus lidské imunodeficience MeSH
- glykoprotein S, koronavirus MeSH
- HIV protilátky MeSH
- imunoglobuliny - Fab fragmenty MeSH
- neutralizující protilátky MeSH
- polysacharidy MeSH
- receptory antigenů B-buněk MeSH
- široce neutralizující protilátky MeSH
- spike protein, SARS-CoV-2 MeSH Prohlížeč
- vakcíny MeSH
HIV-1 envelope (Env) N-glycosylation impact virus-cell entry and immune evasion. How each glycan interacts to shape the Env-protein-sugar complex and affects Env function is not well understood. Here, analysis of two Env variants from the same donor, with differing functional characteristics and N-glycosylation-site composition, revealed that changes to key N-glycosylation sites affected the Env structure at distant locations and had a ripple effect on Env-wide glycan processing, virus infectivity, antibody recognition, and virus neutralization. Specifically, the N262 glycan, although not in the CD4-binding site, modulated Env binding to the CD4 receptor, affected Env recognition by several glycan-dependent neutralizing antibodies, and altered site-specific glycosylation heterogeneity, with, for example, N448 displaying limited glycan processing. Molecular-dynamic simulations visualized differences in glycan density and how specific oligosaccharide positions can move to compensate for a glycan loss. This study demonstrates how changes in individual glycans can alter molecular dynamics, processing, and function of the Env-glycan shield.
- Klíčová slova
- Biochemistry, Biological Sciences, Glycobiology, Microbiology, Virology,
- Publikační typ
- časopisecké články MeSH
Structure-based vaccine design has been used to develop immunogens that display conserved neutralization sites on pathogens such as HIV-1, respiratory syncytial virus (RSV), and influenza. Improving the immunogenicity of these designed immunogens with adjuvants will require formulations that do not alter protein antigenicity. Here, we show that nanoparticle-forming thermoresponsive polymers (TRP) allow for co-delivery of RSV fusion (F) protein trimers with Toll-like receptor 7 and 8 agonists (TLR-7/8a) to enhance protective immunity. Although primary amine conjugation of TLR-7/8a to F trimers severely disrupted the recognition of critical neutralizing epitopes, F trimers site-selectively coupled to TRP nanoparticles retained appropriate antigenicity and elicited high titers of prefusion-specific, TH1 isotype anti-RSV F antibodies following vaccination. Moreover, coupling F trimers to TRP delivering TLR-7/8a resulted in ∼3-fold higher binding and neutralizing antibody titers than soluble F trimers admixed with TLR-7/8a and conferred protection from intranasal RSV challenge. Overall, these data show that TRP nanoparticles may provide a broadly applicable platform for eliciting neutralizing antibodies to structure-dependent epitopes on RSV, influenza, HIV-1, or other pathogens.
- MeSH
- adjuvancia imunologická aplikace a dávkování MeSH
- inbrední kmeny myší MeSH
- lékové transportní systémy metody MeSH
- nanočástice aplikace a dávkování chemie MeSH
- neutralizující protilátky MeSH
- polymery chemie MeSH
- proteiny virové fúze aplikace a dávkování chemie MeSH
- syntetické vakcíny aplikace a dávkování chemie MeSH
- techniky syntetické chemie MeSH
- toll-like receptor 7 agonisté MeSH
- toll-like receptor 8 agonisté MeSH
- vakcíny proti respiračnímu syncyciálnímu viru aplikace a dávkování imunologie farmakologie MeSH
- zvířata MeSH
- Check Tag
- ženské pohlaví MeSH
- zvířata MeSH
- Publikační typ
- časopisecké články MeSH
- práce podpořená grantem MeSH
- Názvy látek
- adjuvancia imunologická MeSH
- F protein, human respiratory syncytial virus MeSH Prohlížeč
- neutralizující protilátky MeSH
- polymery MeSH
- proteiny virové fúze MeSH
- syntetické vakcíny MeSH
- TLR7 protein, human MeSH Prohlížeč
- TLR8 protein, human MeSH Prohlížeč
- toll-like receptor 7 MeSH
- toll-like receptor 8 MeSH
- vakcíny proti respiračnímu syncyciálnímu viru MeSH
