Asymmetric recognition of HIV-1 Envelope trimer by V1V2 loop-targeting antibodies

Haoqing Wang,Michel C Nussenzweig,Harry B Gristick,Michael S Seaman,Rachel P Galimidi,Natalia T Freund,Pamela J Bjorkman,Anthony P West,Louise Scharf

doi:10.7554/elife.27389

Haoqing Wang, Michel C Nussenzweig + Show 7 more

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https://doi.org/10.7554/elife.27389

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Abstract

The HIV-1 envelope (Env) glycoprotein binds to host cell receptors to mediate membrane fusion. The prefusion Env trimer is stabilized by V1V2 loops that interact at the trimer apex. Broadly neutralizing antibodies (bNAbs) against V1V2 loops, exemplified by PG9, bind asymmetrically as a single Fab to the apex of the symmetric Env trimer using a protruding CDRH3 to penetrate the Env glycan shield. Here we characterized a distinct mode of V1V2 epitope recognition by the new bNAb BG1 in which two Fabs bind asymmetrically per Env trimer using a compact CDRH3. Comparisons between cryo-EM structures of Env trimer complexed with BG1 (6.2 Å resolution) and PG9 (11.5 Å resolution) revealed a new V1V2-targeting strategy by BG1. Analyses of the EM structures provided information relevant to vaccine design including molecular details for different modes of asymmetric recognition of Env trimer and a binding model for BG1 recognition of V1V2 involving glycan flexibility.

Highlights

The HIV-1 envelope (Env) glycoprotein trimer, a trimer of gp120-gp41 heterodimers, is the infectious machinery that targets host cell receptors CD4 and CCR5/CXCR4 to mediate fusion between the viral and host membranes (Wyatt and Sodroski, 1998)
The V1V2 epitope on HIV Env is targeted by broadly neutralizing antibodies (bNAbs) that make quaternary interactions that prevent opening of Env trimer to expose the variable 3 (V3) loop and coreceptor binding site, blocking conformational changes leading to fusion of the viral and host cell membranes (McLellan et al, 2011; Pancera et al, 2013; Pan et al, 2015; Walker et al, 2011, 2009; Bonsignori et al, 2011; DoriaRose et al, 2014)
Quaternary interactions visualized far for V1V2 bNAbs involve the binding of a single Fab to the apex of Env trimer (Julien et al, 2013b; Liu et al, 2017), but here we demonstrate that the stoichiometry of binding for the new V1V2 bNAb BG1 (Freund et al, 2017) is two Fabs per Env trimer, with a minor population of 3:1 BG1-Env complexes (Figures 2 and 3; Figure 3— figure supplement 1)

Summary

Introduction

The HIV-1 envelope (Env) glycoprotein trimer, a trimer of gp120-gp heterodimers, is the infectious machinery that targets host cell receptors CD4 and CCR5/CXCR4 to mediate fusion between the viral and host membranes (Wyatt and Sodroski, 1998). As the only viral protein on the surface of HIV-1 virions, Env trimer is the sole target of neutralizing antibodies that prevent infection of host cells (McCoy and Burton, 2017). Most HIV-1 bNAbs exhibit high levels of somatic mutation, and many of these antibodies include long heavy chain complementarity determining region 3 (CDRH3) loops (West et al, 2014). These unusual features appear to be a significant barrier to eliciting such antibodies by immunization

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