Fine epitope signature of antibody neutralization breadth at the HIV-1 envelope CD4-binding site

Abstract

Major advances in donor identification, antigen probe design, and experimental methods to clone pathogen-specific antibodies have led to an exponential growth in the number of newly characterized broadly neutralizing antibodies (bnAbs) that recognize the HIV-1 envelope glycoprotein. Characterization of these bnAbs has defined new epitopes and novel modes of recognition that can result in potent neutralization of HIV-1. However, the translation of envelope recognition profiles in biophysical assays into an understanding of in vivo activity has lagged behind, and identification of subjects and mAbs with potent antiviral activity has remained reliant on empirical evaluation of neutralization potency and breadth. To begin to address this discrepancy between recombinant protein recognition and virus neutralization, we studied the fine epitope specificity of a panel of CD4-binding site (CD4bs) antibodies to define the molecular recognition features of functionally potent humoral responses targeting the HIV-1 envelope site bound by CD4. Whereas previous studies have used neutralization data and machine-learning methods to provide epitope maps, here, this approach was reversed, demonstrating that simple binding assays of fine epitope specificity can prospectively identify broadly neutralizing CD4bs–specific mAbs. Building on this result, we show that epitope mapping and prediction of neutralization breadth can also be accomplished in the assessment of polyclonal serum responses. Thus, this study identifies a set of CD4bs bnAb signature amino acid residues and demonstrates that sensitivity to mutations at signature positions is sufficient to predict neutralization breadth of polyclonal sera with a high degree of accuracy across cohorts and across clades.

Predicting the broadly neutralizing antibody susceptibility of the HIV reservoir

“…Specifically for the CD4bs antibodies, overall correlation of predicted IC50 values was more heterogenous, e.g., VRC01, 3BNC117, and VRC07-523 correlated weakly (spearman r ranging from 0.16 to 0.43), and there was a clear disconnect between N6 and VRC07-523 susceptibilities, for which predicted IC50 values did not correlate (R = 0.03, P = 0.34) (Supplemental Figure 2, C and D), potentially related to the specific mode of recognition of N6, permitting it to avoid steric clashes with glycans in the V5 region of Env (25). These data are consistent with the differing epitope-binding pattern of the CD4bs antibodies (26), corresponding in neutralization susceptibility signatures that are bNAb specific.…”

Relationship between latent and rebound viruses in a clinical trial of anti–HIV-1 antibody 3BNC117

“…We compared the sequences of putative 3BNC117 target sites in env obtained from plasma rebound viruses to Q 2 VOA-derived sequences from the circulating reservoir for the presence of mutations ( Caskey et al, 2015 ; Lynch et al, 2015 ; Bar et al, 2016 ; Scheid et al, 2016 ; Cheng et al, 2018 ). Despite the lack of overlap between the rebound and latent viruses noted above, rebound viruses demonstrated nucleotide and corresponding amino acid variants in the 3BNC117 binding site that preexisted in the latent reservoir.…”

Analysis of HIV-1 latent reservoir and rebound viruses in a clinical trial of anti-HIV-1 antibody 3BNC117

“…We compared the sequences of putative 3BNC117 target sites in env obtained from plasma rebound viruses to Q 2 VOA_derived sequences from the circulating reservoir for the presence of mutations (Bar et al, 2016; Caskey et al, 2015; Cheng et al, 2018; Lynch et al, 2015; Scheid et al, 2016). Despite the lack of overlap between the rebound and latent viruses noted above, rebound viruses demonstrated nucleotide and corresponding amino acid variants in the 3BNC117 binding site that preexisted in the latent reservoir.…”