The HIV-1 Envelope Glycoprotein C3/V4 Region Defines a Prevalent Neutralization Epitope following Immunization

Lin Lei,Yuhe R Yang,Karen Tran,Yimeng Wang,Chi-I Chiang,Gabriel Ozorowski,Yongli Xiao,Andrew B Ward,Richard T Wyatt,Yuxing Li

doi:10.1016/j.celrep.2019.03.039

Abstract

SummaryDespite recent progress in engineering native trimeric HIV-1 envelope glycoprotein (Env) mimics as vaccine candidates, Env trimers often induce vaccine-matched neutralizing antibody (NAb) responses. Understanding the specificities of autologous NAb responses and the underlying molecular mechanisms restricting the neutralization breadth is therefore informative to improve vaccine efficacy. Here, we delineate the response specificity by single B cell sorting and serum analysis of guinea pigs immunized with BG505 SOSIP.664 Env trimers. Our results reveal a prominent immune target containing both conserved and strain-specific residues in the C3/V4 region of Env in trimer-vaccinated animals. The defined NAb response shares a high degree of similarity with the early NAb response developed by a naturally infected infant from whom the HIV virus strain BG505 was isolated and later developed a broadly NAb response. Our study describes strain-specific responses and their possible evolution pathways, thereby highlighting the potential to broaden NAb responses by immunogen re-design.

Highlights

Considerable efforts have been made to design HIV-1 native trimer mimics to induce broadly neutralizing antibody responses in vivo (Sanders and Moore, 2017)
Three BG505-Specific monoclonal antibodies (mAbs) from One Clonal Lineage Recapitulate Serum Autologous Tier 2 Virus Neutralization Capacity In a previous study designed to investigate the immunogenicity of well-ordered trimers displaying different levels of thermostability, guinea pigs were immunized with BG505 SOSIP.664
We used the autologous BG505 SOSIP.664 trimer as the antigen probe to sort antigenspecific class-switched B cells from a single guinea pig (#1567) and cloned 16 mAbs recognizing BG505 SOSIP.664 from 10 million peripheral blood mononuclear cells (PBMCs). None of these 16 mAbs neutralizes the autologous tier 2 virus BG505, while only five of them neutralize tier 1 virus ZM109, recognizing the V3 crown, an immunodominant element of HIV-1 envelope glycoprotein (Env), especially on monomeric gp120, disordered trimers, or ordered trimers that expose this determinant in vivo

Summary

Introduction

Considerable efforts have been made to design HIV-1 native trimer mimics to induce broadly neutralizing antibody (bNAb) responses in vivo (Sanders and Moore, 2017). In HIV-1 infected individuals, such strain-specific NAb responses often appear several months post-infection, which may reflect the initial antibody responses following natural infection (Klasse et al, 2018) These autologous NAbs apply selection pressure on the Env and drive the neutralization escape of circulating viruses, which lead to the development of heterologous or bNAb responses (Anthony et al, 2017; van Haaren et al, 2017; Sather et al, 2014). Studying trimer-induced tier 2 NAb responses in animal models provides an opportunity to characterize the strain-restricted specificities and to compare with the initial NAb responses in natural infection. In conjunction, such parallel efforts could inform future vaccine design or vaccination strategies to expand neutralization breadth

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Discussion

Conclusion