Networks of HIV-1 Envelope Glycans Maintain Antibody Epitopes in the Face of Glycan Additions and Deletions
STRUCTURE
Authors: Seabright, Gemma E.; Cottrell, Christopher A.; van Gils, Marit J.; D'addabbo, Alessio; Harvey, David J.; Behrens, Anna-Janina; Allen, Joel D.; Watanabe, Yasunori; Scaringi, Nicole; Polveroni, Thomas M.; Maker, Allison; Vasiljevic, Snezana; de Val, Natalia; Sanders, Rogier W.; Ward, Andrew B.; Crispin, Max
Abstract
Numerous broadly neutralizing antibodies (bnAbs) have been identified that target the glycans of the HIV-1 envelope spike. Neutralization breadth is notable given that glycan processing can be substantially influenced by the presence or absence of neighboring glycans. Here, using a stabilized recombinant envelope trimer, we investigate the degree to which mutations in the glycan network surrounding an epitope impact the fine glycan processing of antibody targets. Using cryo-electron microscopy and site-specific glycan analysis, we reveal the importance of glycans in the formation of the 2G12 bnAb epitope and show that the epitope is only subtly impacted by variations in the glycan network. In contrast, we show that the PG9 and PG16 glycan-based epitopes at the trimer apex are dependent on the presence of the highly conserved surrounding glycans. Glycan networks underpin the conservation of bnAb epitopes and are an important parameter in immunogen design.
Stabilization of the V2 loop improves the presentation of V2 loop-associated broadly neutralizing antibody epitopes on HIV-1 envelope trimers
JOURNAL OF BIOLOGICAL CHEMISTRY
Authors: de Taeye, Steven W.; Go, Eden P.; Sliepen, Kwinten; de la Pena, Alba Torrents; Badal, Kimberly; Medina-Ramirez, Max; Lee, Wen-Hsin; Desaire, Heather; Wilson, Ian A.; Moore, John P.; Ward, Andrew B.; Sanders, Rogier W.
Abstract
A successful HIV-1 vaccine will likely need to elicit broadly neutralizing antibodies (bNAbs) that target the envelope glycoprotein (Env) spike on the virus. Native-like recombinant Env trimers of the SOSIP design now serve as a platform for achieving this challenging goal. However, SOSIP trimers usually do not bind efficiently to the inferred germline precursors of bNAbs (gl-bNAbs). We hypothesized that the inherent flexibilities of the V1 and V2 variable loops in the Env trimer contribute to the poor recognition of gl-bNAb epitopes at the trimer apex that extensively involve V2 residues. To reduce local V2 flexibility and improve the binding of V2-dependent bNAbs and gl-bNAbs, we designed BG505 SOSIP.664 trimer variants containing newly created disulfide bonds intended to stabilize the V2 loop in an optimally antigenic configuration. The first variant, I184C/E190C, contained a new disulfide bond within the V2 loop, whereas the second variant, E153C/R178C, had a new disulfide bond that cross-linked V2 and V1. The resulting engineered native-like trimer variants were both more reactive with and were neutralized by V2 bNAbs and gl-bNAbs, a finding that may be valuable in the design of germline targeting and boosting trimer immunogens to create an antigenic conformation optimal for HIV vaccine development.
COA
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