Structure-based design of native-like HIV-1 envelope trimers to silence non-neutralizing epitopes and eliminate CD4 binding

Daniel W Kulp,Mia Shin,Michael Kubitz,Christopher A Cottrell,Samantha M Reiss,Natalia De Val,Andrew B Ward,Jon M Steichen,Yumiko Adachi,Jordan R Willis,Alessia Liguori,Matthias Pauthner,Shane Crotty,Dennis R Burton,Xiaozhen Hu,Gabriel Ozorowski,Torben Schiffner,Colin Havenar-Daughton,Oleksandr Kalyuzhniy,Erik Georgeson,William R Schief

doi:10.1038/s41467-017-01549-6

Abstract

Elicitation of broadly neutralizing antibodies (bnAbs) is a primary HIV vaccine goal. Native-like trimers mimicking virion-associated spikes present nearly all bnAb epitopes and are therefore promising vaccine antigens. However, first generation native-like trimers expose epitopes for non-neutralizing antibodies (non-nAbs), which may hinder bnAb induction. We here employ computational and structure-guided design to develop improved native-like trimers that reduce exposure of non-nAb epitopes in the V3-loop and trimer base, minimize both CD4 reactivity and CD4-induced non-nAb epitope exposure, and increase thermal stability while maintaining bnAb antigenicity. In rabbit immunizations with native-like trimers of the 327c isolate, improved trimers suppress elicitation of V3-directed and tier-1 neutralizing antibodies and induce robust autologous tier-2 neutralization, unlike a first-generation trimer. The improved native-like trimers from diverse HIV isolates, and the design methods, have promise to assist in the development of a HIV vaccine.

Highlights

Elicitation of broadly neutralizing antibodies is a primary HIV vaccine goal
While the population dynamics of B cells induced by complex antigens is still not completely understood, it is reasonable to hypothesize that reducing the number of competing, undesired epitopes could alter the specificity of the response and favor the development of antibodies against desired epitopes
BG505 Olio[6] forms homogenous trimers as assessed by SEC-MALS, has a melting temperature of 76 °C (Supplementary Fig. 1 and Supplementary Table 1), and retains a native-like trimer antigenic profile, with high affinity for bnAbs according to SPR and Enzymelinked immuno-sorbent assays (ELISAs) (Fig. 1b, c)

Summary

Introduction

Elicitation of broadly neutralizing antibodies (bnAbs) is a primary HIV vaccine goal. First generation native-like trimers expose epitopes for non-neutralizing antibodies (non-nAbs), which may hinder bnAb induction. Approaches to guide the immune system toward elicitation of a specific bnAb-class such as ‘B-cell lineage vaccine design’[15] or ‘germline-targeting vaccine design’[11,16,17,18,19], often employ very similar envelope sequences in sequential boosting schemes. D Frequency of Env trimer probe positive CD4+ T cells. While the population dynamics of B cells induced by complex antigens is still not completely understood, it is reasonable to hypothesize that reducing the number of competing, undesired epitopes could alter the specificity of the response and favor the development of antibodies against desired epitopes

Objectives

Methods

Results

Conclusion