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. 2013 Sep;87(18):10047-58.
doi: 10.1128/JVI.00984-13. Epub 2013 Jul 10.

Residue-level prediction of HIV-1 antibody epitopes based on neutralization of diverse viral strains

Gwo-Yu Chuang  1 , Priyamvada Acharya, Stephen D Schmidt, Yongping Yang, Mark K Louder, Tongqing Zhou, Young Do Kwon, Marie Pancera, Robert T Bailer, Nicole A Doria-Rose, Michel C Nussenzweig, John R Mascola, Peter D Kwong, Ivelin S Georgiev
Affiliations

Residue-level prediction of HIV-1 antibody epitopes based on neutralization of diverse viral strains

Gwo-Yu Chuang et al. J Virol. 2013 Sep.

Abstract

Delineation of antibody epitopes at the residue level is key to understanding antigen resistance mutations, designing epitope-specific probes for antibody isolation, and developing epitope-based vaccines. Ideally, epitope residues are determined in the context of the atomic-level structure of the antibody-antigen complex, though structure determination may in many cases be impractical. Here we describe an efficient computational method to predict antibody-specific HIV-1 envelope (Env) epitopes at the residue level, based on neutralization panels of diverse viral strains. The method primarily utilizes neutralization potency data over a set of diverse viral strains representing the antigen, and enhanced accuracy could be achieved by incorporating information from the unbound structure of the antigen. The method was evaluated on 19 HIV-1 Env antibodies with neutralization panels comprising 181 diverse viral strains and with available antibody-antigen complex structures. Prediction accuracy was shown to improve significantly over random selection, with an average of greater-than-8-fold enrichment of true positives at the 0.05 false-positive rate level. The method was used to prospectively predict epitope residues for two HIV-1 antibodies, 8ANC131 and 8ANC195, for which we experimentally validated the predictions. The method is inherently applicable to antigens that exhibit sequence diversity, and its accuracy was found to correlate inversely with sequence conservation of the epitope. Together the results show how knowledge inherent to a neutralization panel and unbound antigen structure can be utilized for residue-level prediction of antibody epitopes.

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Figures

Fig 1
Fig 1
Schematic overview of utilizing the mutual variation between amino acid types at each position and neutralization potency for the prediction of epitope residues. For a given antibody, antigen sequence positions are colored according to amino acid type, while each strain is further colored according to neutralization potency.
Fig 2
Fig 2
Six different variants of the neutralization-based epitope prediction method. (A) TP rate at an FP rate level of 0.05 for each of the 19 antibodies, with the average (long black horizontal bar) and standard error (shorter black horizontal bar), for each method variant. The adjusted P value of the pairwise t test between each method and random selection based on the TP rate at an FP rate of 0.05 is displayed. (B) The different types of information that each method variant uses for prediction.
Fig 3
Fig 3
Effect of the number of viral strains and strain diversity on epitope prediction. The average epitope prediction accuracy for 19 HIV-1 antibodies by the SA/nMIproxsum/PS method for panels of different sizes and different degrees of diversity is shown as the average TP rate at the 0.05 FP rate level. The red line represents predictions using different smaller panels constructed by removing sequence-redundant strains with ExPASy. The blue line represents the average prediction accuracy of 100 randomly generated panels for the same panel sizes (error bars indicate standard errors). The orange line represents the prediction accuracy using strains selected only from clade B (16- and 34-strain panels only). The dendrograms display the distribution of the viral strains used in the nonredundant 16-strain panel selected from ExPASy (red) and the clade B 16-strain panel (orange) among all 171 strains (gray).
Fig 4
Fig 4
Relationship between prediction accuracy of the SA/nMIproxsum/PS method and epitope sequence conservation for the 19 HIV-1 antibodies. (A) Fraction of fully conserved residues in the antibody epitopes (horizontal axis) versus TP rate at the 0.05 FP rate level (vertical axis). Two antibodies, PG9 and PG16, were labeled on the y axis since there were no fully conserved residues in their epitopes. A negative correlation was observed between the fraction of fully conserved residues in epitope and the prediction accuracy for a given antibody (P = 0.0093, Deming linear regression). (B) Fraction of fully conserved residues for each of the 19 HIV-1 antibodies. A residue is defined as conserved only if it is 100% conserved among all viral strains in the data set. For example, although 54.55% of the 4E10 epitope residues have a conservation of greater than 98%, only 9.09% of the 4E10 epitope residues are 100% conserved.
Fig 5
Fig 5
Epitope prediction for HIV-1 antibody 8ANC131 using the SA/nMIproxsum/PS method. (A) The top 10 predicted residues (yellow spheres) mapped on a gp120 core crystal structure (red) (PDB ID 3TGT), fitted in an unliganded HIV-1 Env trimer cryo-EM map (EMD accession code 5019, pink). (B) Outline of the top 10 predicted epitope residues (yellow) for 8ANC131 shown on a transparent surface and cartoon representation of gp120 (red). The top 10 predicted epitope residues can be clustered into three distinct sites outlined by yellow dashed circles. (C) ELISA binding of 8ANC131 to YU2 gp120, YU2 gp120 R456S, YU2 gp120 K282N, YU2 gp120 D78N, and YU2 gp120 I326T. Mutants R456S and K282N had a substantially decreased binding to 8ANC131. (D) Prediction accuracy determined by comparison to the complex structure. Shown are the TP rates at different FP rate levels (0.05, 0.10, 0.15, 0.20, and 0.25).
Fig 6
Fig 6
Epitope prediction for HIV-1 antibody 8ANC195 using the SA/nMIproxsum/PS method. (A) The top 10 predicted residues (yellow spheres) mapped on a gp120 core crystal structure (red) (PDB ID 3TGT), fitted in an unliganded HIV-1 Env trimer cryo-EM map (EMD accession code 5019, pink). (B) Outline of the top 10 predicted epitope residues (yellow) for 8ANC195 shown on a transparent surface and cartoon representation of gp120 (red). Two N-linked glycosylation sites, at residues 234 and 276, were among the selected residues; the N-acetylglucosamine moieties linked directly to the two residues are shown in green sticks to highlight their location. (C) ELISA binding of 8ANC195 to the stabilized gp120 core 2CC, 2CC N234S, 2CC T236K, 2CC N276D, and deglycosylated 2CC (2CC degly). 8ANC195 showed good binding to the wild type but did not bind deglycosylated 2CC. The mutations N234S, T236K, and N276D, each of which resulted in the removal of an N-linked glycan, knocked out binding of 2CC to 8ANC195. (D) 8ANC195 neutralization of wild-type, N234S, T236K, and N276D 3337.V2.C6. Wild-type 3337.V2.C6 was potently neutralized by 8ANC195, while all of the N234S, T236K, and N276D mutant viruses were resistant to neutralization by that antibody.
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