Recent progress in broadly neutralizing antibodies to HIV

Abstract

In this Review, we highlight some recent developments in the discovery and application of broadly neutralizing antibodies (bnAbs) to human immunodeficiency virus (HIV); i.e., antibodies able to neutralize diverse isolates of HIV. We consider the characterization of novel bnAbs, recent data on the effects of bnAbs in vivo in humans and animal models, and the importance of both kinds of data for the application of Abs to prophylaxis and therapy and to guide vaccine design. We seek to place newly discovered bnAbs in the context of existing bnAbs, and we explore the various characteristics of the antibodies that are most desirable for different applications.

Fig. 1 |. Neutralization coverage of large panels of global isolates by bnAbs as a function of neutralization potency.

Neutralization was measured through the use of pseudoviruses in a TZM-bl assay and is presented as potency (geometric mean (geomean) IC₅₀, in μg/ml) of newly discovered bnAbs (bold) and earlier bnAbs (less intense), grouped by epitope targeted (colors in key, top right), as in Table 1. Symbols (key, right) indicate ‘elicitability’: Abs with ≥15% overall nucleotide mutation in the heavy and light chain combined, indels or CDR3 length frequencies (CDRH3 or CDRL3) <1% that of the Ab repertoire are least favorably elicited; Abs with ≤15% overall nucleotide mutation in the heavy and light chain combined, no indels and CDR3 length frequencies >1% that of the Ab repertoire are more favorable (‘realistic Abs’); Abs with ≤15% overall nucleotide mutation in the heavy and light chain combined, no indels and CDR3 length frequencies >5% that of the Ab repertoire are most favorable (‘realistic Abs’; this includes only three bnAbs here). The CDRH3 length-frequency cut-offs for comparison with those above are as follows. About 97% of Abs in the human repertoire have a CDRH3 length between 8 and 23 amino acids, and each length is represented at least 1% or more in the repertoire. About 73% of Abs in the repertoire range between 11 and 18 amino acids, and each length is represented at least 5% or more in the repertotire. Correspondingly, about 99% of the λ-CDRL3 lengths range between 8 and 13 amino acids, with each length represented at 1% or more, and 96% range between 9 and 12 amino acids, with each length represented at 5% or more. For the κ-CDRL3, 98% range between 8 and 11 amino acids, with each length represented at 1% or more, and 94% range between 8 and 10 amino acids, with each length represented at 5% or more.

Fig. 2 |. The bnAb epitopes on the HIV env trimer.

Amino-acid residues and glycans comprising epitope regions of SOSIP.664 gp140 trimers of the HIV isolate BG505 (BG505 SOSIP.664) that is targeted by bnAbs, in a side view (top) and top view (bottom); colors indicate epitope regions: blue, V2 apex; purple, V3 glycan; green, CD4bs; dark gray, silent face; red, interface–FP; and yellow, MPER.

Fig. 3 |. Serum concentration of bnAbs needed to provide complete protection against viral challenge.

Serum concentrations of bnAbs (measured immediately before the time of mucosal challenge) plotted against neutralization (measured using challenge virus in a TZM-bl assay) for various challenge SHIVs and Ab doses (in plot; key), showing that the serum concentration of bnAbs required for complete protection against viral challenge in 100% of animals (vertical axis) in the SHIV–macaque model is directly related to the in vitro neutralizing titer (horizontal axis).

Fig. 4 |. Predicted protection coverage in humans by bnAbs, determined from neutralization coverage and titers and available SHIV protection data.

Protection coverage (% value; bottom two rows below plot) against global isolates was estimated on the basis of the ability of the bnAb (horizontal axis) to protect 100% of rhesus macaques at a given serum concentration (first row below plot) and the neutralization potency of the bnAb against the challenge virus. For PGT121, a serum concentration of 15 μg/ml or 22 μg/ml was required for sterilizing immunity against virus challenge with SHIV-SF162P3 or SHIV-AD8EO, respectively. The neutralization IC₅₀ of PGT121 against these challenge SHIVs on TZM-bl cells was measured to be 0.03 μg/ml for SF162P3 and 0.20 μg/ml for AD8EO. On the basis of neutralization breadth and potency on cross-clade virus panels, PGT121 can neutralize 36% of viruses at an IC₅₀ of 0.03 μg/ml or less and can neutralize 50% of viruses at an IC₅₀ of 0.20 μg/ml or less. Accordingly, we estimate PGT121 would provide 36% protection coverage if it were elicited by vaccination at a serum concentration of 15 μg/ml (on the basis of data for SHIV-SF162P3) and to provide 50% protection coverage if elicited at a concentration of 22 μg/ml (data for SHIV-AD8EO data). We also provide estimated protection coverage if each mAb or combinations of mAbs were elicited at a serum concentration of 30 μg/ml, as a reasonable sustained concentration of Abs elicited by vaccination. In the plot, each symbol represents a unique SHIV isolate (194–200 isolates tested per Ab), with colors (key) indicating the epitope targeted by the Ab (along horizontal axis; SHIV below), and each symbol position represents the neutralization IC₅₀ in the TZM-bl assay (vertical axis).