Neutralizing Antibody Responses Induced by HIV-1 Envelope Glycoprotein SOSIP Trimers Derived from Elite Neutralizers.

Anna Schorcht,Max Crispin,Gabriel Ozorowski,Steven W De Taeye,Christopher A Cottrell,John P Moore,Hanneke Schuitemaker,Natalia De Val,Celia C Labranche,Andrew B Ward,Rogier W Sanders,David C Montefiori,Marit J Van Gils,Per Johan Klasse,Joel D Allen,Jonathan L Torres,Anila Yasmeen,Judith A Burger,Alba Torrents De La Peña,Edith E Schermer,Ilja Bontjer,Anna‐Janina Behrens ,Stephanie B H Gumbs ,Tom L.g.m Van Den Kerkhof

doi:10.1128/jvi.01214-20

Abstract

The induction of broadly neutralizing antibodies (bNAbs) is a major goal in vaccine research. HIV-1-infected individuals that develop exceptionally strong bNAb responses, termed elite neutralizers, can inform vaccine design by providing blueprints for the induction of similar bNAb responses. We describe a new recombinant native-like envelope glycoprotein (Env) SOSIP trimer, termed AMC009, based on the viral founder sequences of an elite neutralizer. The subtype B AMC009 SOSIP protein formed stable native-like trimers that displayed multiple bNAb epitopes. Overall, its structure at 4.3-Å resolution was similar to that of BG505 SOSIP.664. The AMC009 trimer resembled one from a second elite neutralizer, AMC011, in having a dense and complete glycan shield. When tested as immunogens in rabbits, the AMC009 trimers did not induce autologous neutralizing antibody (NAb) responses efficiently while the AMC011 trimers did so very weakly, outcomes that may reflect the completeness of their glycan shields. The AMC011 trimer induced antibodies that occasionally cross-neutralized heterologous tier 2 viruses, sometimes at high titer. Cross-neutralizing antibodies were more frequently elicited by a trivalent combination of AMC008, AMC009, and AMC011 trimers, all derived from subtype B viruses. Each of these three individual trimers could deplete the NAb activity from the rabbit sera. Mapping the polyclonal sera by electron microscopy revealed that antibodies of multiple specificities could bind to sites on both autologous and heterologous trimers. These results advance our understanding of how to use Env trimers in multivalent vaccination regimens and the immunogenicity of trimers derived from elite neutralizers.IMPORTANCE Elite neutralizers, i.e., individuals who developed unusually broad and potent neutralizing antibody responses, might serve as blueprints for HIV-1 vaccine design. Here, we studied the immunogenicity of native-like recombinant envelope glycoprotein (Env) trimers based on viral sequences from elite neutralizers. While immunization with single trimers from elite neutralization did not recapitulate the breadth and potency of neutralization observed in these infected individuals, a combination of three subtype B Env trimers from elite neutralizers resulted in some neutralization breadth within subtype B viruses. These results should guide future efforts to design vaccines to induce broadly neutralizing antibodies.

Highlights

We previously found that trivalent and tetravalent combinations of SOSIP trimers from subtypes A, B, and C did not elicit heterologous neutralizing antibody (NAb) effectively, because autologous NAbs against the glycan holes present on the individual trimers seem to dominate over cross-reactive responses [30, 31]
One underlying reason for selecting the AMC009 and AMC011 sequences was the hypothesis that early env sequences from elite neutralizers are more efficient at inducing broadly neutralizing antibodies (bNAbs), especially if they possess an intact glycan shield [9, 33, 56]
Both AMC009 and AMC011 SOSIP-immunized animals developed poor autologous NAb responses compared to the BG505 and B41 SOSIP-immunized animals, which probably can be explained by the absence of immunodominant glycan holes that usually dominate the induction of strain-specific autologous NAb responses against SOSIP trimers [20, 44, 58]

Summary

Introduction

We found that the trivalent combination, in contrast to the AMC009 trimer alone, elicited antibodies that targeted different regions on SOSIP trimers and that occasionally cross-neutralized heterologous tier 2 viruses [19, 33]. SOSIP trimers derived from elite neutralizers might give rise to bNAbs. Second, Env trimers without immunodominant glycan holes might induce a heterologous NAb response instead of a strain-specific autologous response.

Results

Conclusion