Improving the Immunogenicity of Native-like HIV-1 Envelope Trimers by Hyperstabilization

Alba Torrents De La Peña,Charlotte D Vavourakis,Edith E Schermer,Jonathan L Torres,Andrew B Ward,John P Moore,Rogier W Sanders,Gabriel Ozorowski,Pavel Pugach,Laura K Pritchard,Steven W De Taeye,Kwinten Sliepen,Jean-Philippe Julien,Thomas J Ketas,Max Crispin,Heather Desaire,Anila Yasmeen,Per Johan Klasse,David C Montefiori,Eden P Go,Kelly K Lee,Christopher A Cottrell,Ian A Wilson,Marit J Van Gils,Judith A Burger,Celia C Labranche ,Miklós Guttman ,Anna‐Janina Behrens ,Fernando Garcés

doi:10.1016/j.celrep.2017.07.077

Abstract

SummaryThe production of native-like recombinant versions of the HIV-1 envelope glycoprotein (Env) trimer requires overcoming the natural flexibility and instability of the complex. The engineered BG505 SOSIP.664 trimer mimics the structure and antigenicity of native Env. Here, we describe how the introduction of new disulfide bonds between the glycoprotein (gp)120 and gp41 subunits of SOSIP trimers of the BG505 and other genotypes improves their stability and antigenicity, reduces their conformational flexibility, and helps maintain them in the unliganded conformation. The resulting next-generation SOSIP.v5 trimers induce strong autologous tier-2 neutralizing antibody (NAb) responses in rabbits. In addition, the BG505 SOSIP.v6 trimers induced weak heterologous NAb responses against a subset of tier-2 viruses that were not elicited by the prototype BG505 SOSIP.664. These stabilization methods can be applied to trimers from multiple genotypes as components of multivalent vaccines aimed at inducing broadly NAbs (bNAbs).

Highlights

Despite many attempts, no experimental vaccine has induced strongly protective immunity against HIV-1 infection
We have described a soluble, recombinant envelope glycoprotein (Env) trimer, BG505 SOSIP.664, that is stabilized by a disulfide bond between glycoprotein120 and gp41 and an Ile-to-Pro substitution at position 559 in gp41 (Binley et al, 2000; Sanders et al, 2002, 2013)
New disulfide bonds were evaluated in the absence of the SOS bond, and a few promising candidates were subsequently chosen to make double disulfide-bond variants (Figures S1 and S2)

Summary

Introduction

No experimental vaccine has induced strongly protective immunity against HIV-1 infection. One approach to this problem is the generation of an envelope glycoprotein (Env)-based vaccine that induces broadly neutralizing antibodies (bNAbs) (van Gils and Sanders, 2013). The NAb activity in four other rabbits tested, two receiving SOSIP.v5.2 and two receiving SOSIP.v6 (animals 1831 and 1833), were much less affected by the PNGSs knockin mutations, showing that the NAb response in those rabbits was only partly directed to the 241/289 glycan hole. The finding that introduction of the PNGSs at 241 and 289 only had a partial effect on the NAb activity in animals 1831 and 1833 is consistent with the observation that the gp120-7C3 protein did not deplete the NAb activity from the sera of these two animals. While the NAb specificities of three SOSIP.v6 recipient animals appear to be directed to the 241/289 glycan hole, those in the two other animals appear to be predominantly targeting an epitope that is affected by residues 354–363

Results

Discussion

Conclusion