To bnAb or Not to bnAb: Defining Broadly Neutralising Antibodies Against HIV-1

Abstract

Since their discovery, antibodies capable of broad neutralisation have been at the forefront of HIV-1 research and are of particular interest due to in vivo passive transfer studies demonstrating their potential to provide protection. Currently an exact definition of what is required for a monoclonal antibody to be classed as a broadly neutralising antibody (bnAb) has not yet been established. This has led to hundreds of antibodies with varying neutralisation breadth being studied and has given insight into antibody maturation pathways and epitopes targeted. However, even with this knowledge, immunisation studies and vaccination trials to date have had limited success in eliciting antibodies with neutralisation breadth. For this reason there is a growing need to identify factors specifically associated with bnAb development, yet to do this a set of criteria is necessary to distinguish bnAbs from non-bnAbs. This review aims to define what it means to be a HIV-1 bnAb by comparing neutralisation breadth, genetic features and epitopes of bnAbs, and in the process highlights the challenges of comparing the array of antibodies that have been isolated over the years.

Keywords: HIV-1; broadly neutralising antibody; complementary determining region; epitope; somatic hypermutation.

Figure 1

Neutralisation breadth corresponds with the ability to target functional Env trimers in a closed conformation. Tier 1A, tier 1B and tier 2/3 viruses have a predominantly open, intermediate and closed Env trimer conformation respectively and relates to their susceptibility to neutralisation, with tier 2/3 viruses being harder to neutralise. Antibodies that can neutralise tier 2/3 viruses from multiple clades (listed here in alphabetical order) have increased breadth by targeting conserved sites on the Env trimer.

Figure 2

Neutralisation breadth and potency of HIV bnAbs against the 118 multi-clade PV panel. (A–C) First generation bnAbs isolated prior to 2009 are shown in grey and second generation bnAbs isolated after 2009 are shown in blue. (A) Dashed lines at 30% neutralisation breadth and potency (geometric mean IC₅₀) of 3.6 µg/ml define the minimum bnAb thresholds for second generation bnAbs (blue circles). (B) Dashed lines at 68% neutralisation breadth and potency (geometric mean IC₅₀) of 0.6 µg/ml define elite bnAbs (orange circles). (C) The diagonal dashed line ranging from 30% to 100% neutralisation breadth and 0.01 µg/ml to 3.6 µg/ml potency (geometric mean IC₅₀) compensates lower neutralisation breadth with lower potency to define elite bnAbs (orange circles). (D) Summary of the criteria that categorises second generation (2^nd Gen) bnAbs in (A) and elite bnAbs in (B, C).

Figure 3

VH mutation frequency, CDRH3 length and neutralisation breadth of HIV bnAbs against the 118 multi-clade PV panel. Mutation frequency was determined from VH nucleotide sequences. Correlations were determined by linear regression analysis, with p<0.05. (A) VH mutation frequency and neutralisation breadth of bnAbs had no association (p=0.099). (B) VH mutation frequency and neutralisation breadth of bnAbs grouped by epitope was associated for gp120-gp41 interface bnAbs (p=0.027). (C) CDRH3 length and neutralisation breadth of bnAbs had no association (p=0.763). (D) CDRH3 length and neutralisation breadth of bnAbs grouped by epitope was associated for high mannose patch bnAbs (p=0.019). (E) Summary of VH mutation frequency and CDRH3 length associations with neutralisation breadth. ns, Not significant.