Rapid and Focused Maturation of a VRC01-Class HIV Broadly Neutralizing Antibody Lineage Involves Both Binding and Accommodation of the N276-Glycan

Jeffrey C Umotoy ,Dennis R Burton,Trevor Biddle,Sergey Menis,Dale Kitchin,Bernard S Bagaya,Sanjay Mohan,Devin Sok,William Kilembe,Torben Schiffner,Molati Nonyane,Bryan Briney,Ben Murrell,Collin Joyce,Elise Landais,Pascal Poignard,William R Schief,Sharon Madzorera,Karen L Saye-Francisco,Penny L Moore,Thomas Vollbrecht,Iavi Protocol C Investigators ,Bronwen E Lambson ,Oleksandr Kalyuzhniy

doi:10.1016/j.immuni.2019.06.004

Abstract

SummaryThe VH1-2 restricted VRC01-class of antibodies targeting the HIV envelope CD4 binding site are a major focus of HIV vaccine strategies. However, a detailed analysis of VRC01-class antibody development has been limited by the rare nature of these responses during natural infection and the lack of longitudinal sampling of such responses. To inform vaccine strategies, we mapped the development of a VRC01-class antibody lineage (PCIN63) in the subtype C infected IAVI Protocol C neutralizer PC063. PCIN63 monoclonal antibodies had the hallmark VRC01-class features and demonstrated neutralization breadth similar to the prototype VRC01 antibody, but were 2- to 3-fold less mutated. Maturation occurred rapidly within ∼24 months of emergence of the lineage and somatic hypermutations accumulated at key contact residues. This longitudinal study of broadly neutralizing VRC01-class antibody lineage reveals early binding to the N276-glycan during affinity maturation, which may have implications for vaccine design.

Highlights

Narrowly neutralizing antibody responses with VRC01-class features in transgenic mouse models (Briney et al, 2016b; Dosenovic et al, 2015; Jardine et al, 2015; McGuire et al, 2016; Sok et al, 2016; Tian et al, 2016)
To isolate the antibodies contributing to the plasma neutralization breadth in this donor, we used the previously described recombinant HIV envelope glycoprotein (Env) WT and D368R (CD4bs epitope knock-out) proteins (Li et al, 2012)
These include mutations in HCDR1 and HCDR2, which are important for high-affinity binding to the gp120-Loop D and CD4 receptor binding site (CD4bs)-loop, and mutations in LCDR1 and LFR3 which reduce the steric clash with the N276and N462-glycans on Env (Figure S2) (Zhou et al, 2015; Jardine et al, 2016b)

Summary

Introduction

Narrowly neutralizing antibody responses with VRC01-class features in transgenic mouse models (Briney et al, 2016b; Dosenovic et al, 2015; Jardine et al, 2015; McGuire et al, 2016; Sok et al, 2016; Tian et al, 2016). Comparison between VRC01-class antibodies (Briney et al, 2016b; Jardine et al, 2013; McGuire et al, 2013) and subsequent design of minimally mutated VRC01-class antibodies (Jardine et al, 2016b) highlighted the functional role of key ‘‘patches’’ of SHM that contribute to neutralization breadth and potency The importance of these mutations was confirmed by comparing to the relatively strain-specific neutralizing DRVI07 antibody lineage, which harbored all the distinguishing features of VRC01-class antibodies except for the SHM in the light chain needed to accommodate the N276- and N462- glycans adjacent to the CD4bs (Kong et al, 2016). These data indicate that accommodation of the glycans surrounding the CD4bs is a major hurdle for acquiring neutralization breadth that is typical for VRC01-class antibodie

Methods

Results

Discussion

Conclusion