Drift of the HIV-1 envelope glycoprotein gp120 toward increased neutralization resistance over the course of the epidemic: a comprehensive study using the most potent and broadly neutralizing monoclonal antibodies

Abstract

Extending our previous analyses to the most recently described monoclonal broadly neutralizing antibodies (bNAbs), we confirmed a drift of HIV-1 clade B variants over 2 decades toward higher resistance to bNAbs targeting almost all the identified gp120-neutralizing epitopes. In contrast, the sensitivity to bNAbs targeting the gp41 membrane-proximal external region remained stable, suggesting a selective pressure on gp120 preferentially. Despite this evolution, selected combinations of bNAbs remain capable of neutralizing efficiently most of the circulating variants.

FIG 1

Enhanced resistance of early/transmitted HIV-1 clade B variants to neutralization by monoclonal NAbs (MoNAbs) over the course of the epidemic. Comparisons are shown for the neutralization sensitivity of Env-pseudotyped viruses derived from historical patients (HP; n = 11), intermediate patients (IP; n = 15), and contemporary patients (CP; n = 14) by the following groups of antibodies: b12, VRC01, VRC03, and NIH45-46^G54W (adapted from reference 33) and NIH45-46m2, NIH45-46m7, and 3BNC117 (this study) (A); PGT145, PG9, and PG16 (adapted from reference 33) and PG9-16-RSH, PG9-iMab, PG16-iMab, and iMab (this study) (B); PGT135, PGT121, and PGT128 (adapted from reference 33) and 10-1074 (this study) (C); 2G12 (adapted from reference 33) and 8ANC195 and JM4sdAb (this study) (D); 4E10 and 2F5 (adapted from reference 33) and 10E8 (this study) (D). Box plots show the distributions of antibody titers (IC₅₀s) of each bNAb toward pseudotyped viruses of each period; the horizontal lines represent the 10th, median, and 90th percentiles. Each datum point represents the mean value of the assay performed in duplicate. Differences of neutralization sensitivity between viruses over calendar time were evaluated using a Jonckheere-Terpstra test.

FIG 2

Potency and breadth comparison of bNAbs against early/transmitted HIV-1 variants. (A) A heat map of the neutralizing activities (IC₅₀s) of the bNAbs against a panel of 40 pseudotyped viruses from patients with primary infection (HP, IP, and CP), with increasingly darker colors indicating increasing neutralization sensitivity, as indicated by the key. (B) Neutralization breadth of bNAbs against the panel of pseudotyped viruses. Percentages of viruses neutralized for each bNAb at less than 1 μg/ml are indicated above the graph. IC₅₀s greater than the highest bNAb concentration tested (10 μg/ml) were assigned a value of 10 in the geometric mean IC₅₀ calculations.

FIG 3

Neutralization coverage of the most recently transmitted HIV-1 variants. (A) Coverage graph comparing the neutralization breadth and potencies of bNAbs against pseudotyped viruses from contemporary patients. The y axis shows the cumulative frequency of IC₅₀s up to the concentration shown on the x axis. (B) Bar graph showing values for the area under the curve for the bNAbs shown in the coverage graph. (C) The neutralization coverage of viruses from contemporary patients was tested against a 1:1:1 combination of NIH45-46m2, 10-1074, and 10E8. Solid lines show the coverage of each bNAb used alone or in combination (experimental association). Each datum point represents the mean value of the assay performed in duplicate. The dashed line shows the theoretical coverage that would be obtained if the neutralizing activities of combined antibodies were fully additive. (D) Bar graph showing values for the area under the curve for the bNAbs used alone or in combination, as shown in the coverage graph.