Enhancing and shaping the immunogenicity of native-like HIV-1 envelope trimers with a two-component protein nanoparticle

Philip J.m Brouwer ,John P Moore,Daniel Ellis,Iván Del Moral-Sánchez,Neil P King,Aleksandar Antanasijevic,Miguel Camacho,Christopher A Cottrell,Marco Catalano,Anna‐Janina Behrens ,Thomas J Ketas,Lance Stewart ,Anila Yasmeen,Marit J Van Gils,Max Crispin,Zachary T Berndsen ,Jacob B Bale,David Baker,Kwinten Sliepen,Andrew B Ward,Tom P L Bijl,David C Montefiori,Joel D Allen,Anna Schorcht,William Sheffler,Ilja Bontjer,Brooke Fiala,Celia C Labranche ,Judith A Burger,Per Johan Klasse,Rogier W Sanders

doi:10.1038/s41467-019-12080-1

Abstract

The development of native-like HIV-1 envelope (Env) trimer antigens has enabled the induction of neutralizing antibody (NAb) responses against neutralization-resistant HIV-1 strains in animal models. However, NAb responses are relatively weak and narrow in specificity. Displaying antigens in a multivalent fashion on nanoparticles (NPs) is an established strategy to increase their immunogenicity. Here we present the design and characterization of two-component protein NPs displaying 20 stabilized SOSIP trimers from various HIV-1 strains. The two-component nature permits the incorporation of exclusively well-folded, native-like Env trimers into NPs that self-assemble in vitro with high efficiency. Immunization studies show that the NPs are particularly efficacious as priming immunogens, improve the quality of the Ab response over a conventional one-component nanoparticle system, and are most effective when SOSIP trimers with an apex-proximate neutralizing epitope are displayed. Their ability to enhance and shape the immunogenicity of SOSIP trimers make these NPs a promising immunogen platform.

Highlights

The development of native-like HIV-1 envelope (Env) trimer antigens has enabled the induction of neutralizing antibody (NAb) responses against neutralization-resistant HIV1 strains in animal models
They can be taken up by antigen-presenting cells and trafficked to lymph nodes more efficiently, leading to improved formation of germinal centers[13,14,15,16]. This category of immunogen may be valuable for priming responses, because the avidity advantage conferred by multivalent presentation may compensate for interactions with the B-cell receptors (BCRs) of naive B cells, which tend to be of low affinity
An early screen for the expression of several of our designed nanoparticle components fused to BG505 SOSIP revealed that the trimeric component of the recently described NP I53-5030, designated I53-50A, secreted at higher levels than any other scaffold when fused to BG505 SOSIP

Summary

Introduction

The development of native-like HIV-1 envelope (Env) trimer antigens has enabled the induction of neutralizing antibody (NAb) responses against neutralization-resistant HIV1 strains in animal models. Immunization studies show that the NPs are efficacious as priming immunogens, improve the quality of the Ab response over a conventional one-component nanoparticle system, and are most effective when SOSIP trimers with an apex-proximate neutralizing epitope are displayed. Immunogens intended to induce bNAbs are all based on the viral envelope glycoproteins (Env) and an increasingly commonly used design platform involves SOSIP trimers, which are recombinant, soluble mimics of Env[3,4,5] Despite their ability to elicit autologous NAbs against resistant (Tier-2) HIV-1 strains in animal models, further improvements to the design and delivery of SOSIP trimers are required to increase the potency, longevity, and breadth of NAb responses[6,7,8]. The practicalities of producing liposome-based immunogens on a large scale for human trials remain to be addressed

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