Epitopes for neutralizing antibodies induced by HIV-1 envelope glycoprotein BG505 SOSIP trimers in rabbits and macaques.

Per Johan Klasse ,Andrew B Ward,Gabriel Ozorowski,Bali Pulendran,Guido Silvestri,Diawoye Camara,Dan H Barouch,Thomas J Ketas,Celia C Labranche,Shane Crotty,John P Moore,Pavel Pugach,Gargi Debnath,Erik Francomano,Christine A Bricault,Rogier W Sanders,Ian A Wilson,Rajesh P Ringe,Marit J Van Gils,David C Montefiori,Christopher A Cottrell,Sudhir Pai Kasturi

doi:10.1371/journal.ppat.1006913

Abstract

The native-like, soluble SOSIP.664 trimer based on the BG505 clade A env gene of HIV-1 is immunogenic in various animal species, of which the most studied are rabbits and rhesus macaques. The trimer induces autologous neutralizing antibodies (NAbs) consistently but at a wide range of titers and with incompletely determined specificities. A precise delineation of immunogenic neutralization epitopes on native-like trimers could help strategies to extend the NAb response to heterologous HIV-1 strains. One autologous NAb epitope on the BG505 Env trimer is known to involve residues lining a hole in the glycan shield that is blocked by adding a glycan at either residue 241 or 289. This glycan-hole epitope accounts for the NAb response of most trimer-immunized rabbits but not for that of a substantial subset. Here, we have used a large panel of mutant BG505 Env-pseudotyped viruses to define additional sites. A frequently immunogenic epitope in rabbits is blocked by adding a glycan at residue 465 near the junction of the gp120 V5 loop and β24 strand and is influenced by amino-acid changes in the structurally nearby C3 region. We name this new site the “C3/465 epitope”. Of note is that the C3 region was under selection pressure in the infected infant from whom the BG505 virus was isolated. A third NAb epitope is located in the V1 region of gp120, although it is rarely immunogenic. In macaques, NAb responses induced by BG505 SOSIP trimers are more often directed at the C3/465 epitope than the 241/289-glycan hole.

Highlights

As immune responses in monkeys are the more likely to resemble those in humans, the findings described here might aid strategies to steer human antibody responses to sites that are cross-reactive among HIV strains
The induction of neutralizing-antibody responses against human immunodeficiency virus type 1 (HIV-1) is the objective of vaccine programs based on various soluble envelope glycoprotein (Env) trimers
It is well known that antigenicity does not equal immunogenicity: the presence of a bNAb epitope on an Env trimer does not ensure that neutralizing antibodies (NAbs) will be raised against it [3, 4, 26,27,28]

Summary

Introduction

The induction of neutralizing-antibody responses against human immunodeficiency virus type 1 (HIV-1) is the objective of vaccine programs based on various soluble envelope glycoprotein (Env) trimers (reviewed in [1,2,3,4,5,6,7,8,9,10,11,12]). The prototype native-like recombinant Env trimer is the BG505 SOSIP.664 construct, which is based on a clade A env gene [13,14,15,16]. This trimer, like many subsequent ones of similar design from multiple genotypes, mimics the native structure of the Env spikes on the surface of HIV-1 virions that are targeted by neutralizing antibodies, NAbs [15, 17,18,19,20]. It is well known that antigenicity does not equal immunogenicity: the presence of a bNAb epitope on an Env trimer does not ensure that NAbs will be raised against it [3, 4, 26,27,28]

Methods

Results

Discussion

Conclusion