Abstract
A substantial fraction of broadly neutralizing antibodies (bnAbs) in certain HIV-infected donors recognizes glycan-dependent epitopes on HIV-1 gp120. Here, we elucidate how bnAb PGT 135 recognizes its Asn332 glycan-dependent epitope from its crystal structure with gp120, CD4 and Fab 17b at 3.1 Å resolution. PGT 135 interacts with glycans at Asn332, Asn392 and Asn386, using long CDR loops H1 and H3 to penetrate the glycan shield to access the gp120 protein surface. Electron microscopy reveals PGT 135 can accommodate the conformational and chemical diversity of gp120 glycans by altering its angle of engagement. The combined structural studies of PGT 135, PGT 128 and 2G12 show this Asn332-dependent epitope is highly accessible and much more extensive than initially appreciated, allowing for multiple binding modes and varied angles of approach, thereby representing a supersite of vulnerability for antibody neutralization.
Highlights
Given that neutralizing antibody selection pressure shifts glycosylation sites on the virus during the course of infection[2], it is reasonable to assume that these antibodies may be targeting protein surfaces near glycans, and the glycans themselves
This notion is supported by observations of serum neutralizing activity that is dependent on the presence of the glycan attached to Asn3327-10 and by the recent discovery of several broadly neutralizing antibodies that interact with gp[120] in a glycan-dependent manner
The JR-FL gp[120] monomeric core bound to PGT 135 Fab with high affinity [82 nM by Isothermal titration calorimetry (ITC) (Supplementary Table 1)], but the corresponding virus was only weakly neutralized by PGT 135 IgG unless specific mutations were introduced into the V1-V2 loops, which are >25 Å away from the epitope in the monomeric gp[120] structure and probably affect binding indirectly by impacting trimer interactions (Fig. 2)[19]
Summary
Given that neutralizing antibody selection pressure shifts glycosylation sites on the virus during the course of infection[2], it is reasonable to assume that these antibodies may be targeting protein surfaces near glycans, and the glycans themselves. This notion is supported by observations of serum neutralizing activity that is dependent on the presence of the glycan attached to Asn3327-10 and by the recent discovery of several broadly neutralizing antibodies (bnAb) that interact with gp[120] in a glycan-dependent manner. The Asn332-dependent epitope constitutes a major site of vulnerability on the glycosylated face of gp[120] that can be accessed by antibodies from different germline precursors using completely different modes of recognition and, most likely, different mechanisms of neutralization
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