The C3/465 glycan hole cluster in BG505 HIV-1 envelope is the major neutralizing target involved in preventing mucosal SHIV infection.

Tysheena P Charles,Antu K Dey,Sailaja Gangadhara,George M Shaw,Bali Pulendran,Venkata S Bollimpelli,Christopher A Cottrell,Cynthia A Derdeyn,Eric Hunter,Samantha L Burton,Rama R Amara,Leigh M Sewall,Prabhu S Arunachalam,Marit J Van Gils,Andrew B Ward,Thomas J Hope

doi:10.1371/journal.ppat.1009257

Abstract

Stabilized HIV-1 envelope (Env) trimers elicit tier 2 autologous neutralizing antibody (nAb) responses in immunized animals. We previously demonstrated that BG505 SOSIP.664.T332N gp140 (BG505 SOSIP) immunization of rhesus macaques (RM) provided robust protection against autologous intra-vaginal simian-human immunodeficiency virus (SHIV) challenge that was predicted by high serum nAb titers. Here, we show that nAb in these protected RM targeted a glycan hole proximal to residue 465 in gp120 in all cases. nAb also targeted another glycan hole at residues 241/289 and an epitope in V1 at varying frequencies. Non-neutralizing antibodies directed at N611-shielded epitopes in gp41 were also present but were more prevalent in RM with low nAb titers. Longitudinal analysis demonstrated that nAb broadened in some RM during sequential immunization but remained focused in others, the latter being associated with increases in nAb titer. Thirty-eight monoclonal antibodies (mAbs) isolated from a protected RM with an exceptionally high serum neutralization titer bound to the trimer in ELISA, and four of the mAbs potently neutralized the BG505 Env pseudovirus (PV) and SHIV. The four neutralizing mAbs were clonally related and targeted the 465 glycan hole to varying degrees, mimicking the serum. The data demonstrate that the C3/465 glycan hole cluster was the dominant neutralization target in high titer protected RM, despite other co-circulating neutralizing and non-neutralizing specificities. The isolation of a neutralizing mAb family argues that clonotype expansion occurred during BG505 SOSIP immunization, leading to high titer, protective nAb and setting a desirable benchmark for HIV vaccines.

Highlights

Successful vaccines have been developed against many viral pathogens by inducing neutralizing antibody (nAb) responses that protect against infection [1]
When we mapped the neutralizing antibody responses using viral mutants, we found that they mainly targeted one exposed region of the HIV-1 envelope protein that is unique to the strain we used in the vaccine
We previously demonstrated in our preclinical efficacy study that BG505 SOSIP immunization of rhesus macaques (RM) provided statistically significant protection against ten intra-vaginal challenges with BG505 simian-human immunodeficiency virus (SHIV) [9]

Summary

Introduction

Successful vaccines have been developed against many viral pathogens by inducing nAb responses that protect against infection [1]. The exposure of irrelevant epitopes on monomeric and poorly trimeric Env vaccine immunogens is an obstacle for eliciting tier 2 neutralizing antibodies; the development of stabilized, native-like gp140 trimers has provided a major advance [3,4,5]. Native-like SOSIP trimers have elicited antibodies with tier 2 autologous neutralizing capacity in small animal models and in RM [6,7,8,9]. A recent study provided evidence that high serum nAb 50% inhibitory dilution (ID50) titers elicited by BG505 SOSIP were associated with protection against repeated, low dose intra-rectal SHIV.BG505 challenges [10]. Immunization resulted in robust and significant protection against repeated, low dose intra-vaginal SHIV.BG505 challenges in both vaccination arms, compared to the controls [9]. A serum ID50 titer greater than 1:319 at the antibody peak, two weeks after final immunization, was completely predictive of protection, prompting us to examine in greater detail the specificities and characteristics of nAb associated with preventing acquisition

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Conclusion