Abstract
SummaryNumerous 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.
Highlights
The envelope spike (Env) of the human immunodeficiency virus type 1 (HIV-1) mediates infection of target host cells and is a main target for vaccine design
Whereas the Env glycan shield typically limits antibody neutralization, many broadly neutralizing antibody (bnAb) have, paradoxically, evolved to recognize epitopes that are either entirely or partially composed of N-linked glycans (Blattner et al, 2014; Doores and Burton, 2010; Falkowska et al, 2014; Huang et al, 2014; McLellan et al, 2011; Pancera et al, 2013; Pejchal et al, 2011; Scharf et al, 2014; Walker et al, 2009, 2011). These bnAbs recognize the glycans at four distinct regions of Env: the gp120/gp41 protomer interface (e.g., PGT151), surrounding the CD4 binding site (e.g., HJ16), the V1/V2 loops at the trimer apex (e.g., PG9 and PG16), and the oligomannose-type glycans centered around the highly conserved N332 site on the outer domain of gp120 (e.g., PGT135 and 2G12) (Crispin et al, 2018)
We report a high-resolution structure of the 2G12 bnAb in complex with the BG505 SOSIP.664 trimer by cryo-electron microscopy and reveal details of the wider network of glycans that maintain the epitope
Summary
The envelope spike (Env) of the human immunodeficiency virus type 1 (HIV-1) mediates infection of target host cells and is a main target for vaccine design. Whereas the Env glycan shield typically limits antibody neutralization, many bnAbs have, paradoxically, evolved to recognize epitopes that are either entirely or partially composed of N-linked glycans (Blattner et al, 2014; Doores and Burton, 2010; Falkowska et al, 2014; Huang et al, 2014; McLellan et al, 2011; Pancera et al, 2013; Pejchal et al, 2011; Scharf et al, 2014; Walker et al, 2009, 2011). Given the number of bnAbs targeting the N332 glycan, it has previously been termed the ‘‘supersite of immune vulnerability’’ (Kong et al, 2013)
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