Identification of broadly neutralizing antibody epitopes in the HIV-1 envelope glycoprotein using evolutionary models

Abstract

BackgroundIdentification of the epitopes targeted by antibodies that can neutralize diverse HIV-1 strains can provide important clues for the design of a preventative vaccine.MethodsWe have developed a computational approach that can identify key amino acids within the HIV-1 envelope glycoprotein that influence sensitivity to broadly cross-neutralizing antibodies. Given a sequence alignment and neutralization titers for a panel of viruses, the method works by fitting a phylogenetic model that allows the amino acid frequencies at each site to depend on neutralization sensitivities. Sites at which viral evolution influences neutralization sensitivity were identified using Bayes factors (BFs) to compare the fit of this model to that of a null model in which sequences evolved independently of antibody sensitivity. Conformational epitopes were identified with a Metropolis algorithm that searched for a cluster of sites with large Bayes factors on the tertiary structure of the viral envelope.ResultsWe applied our method to ID50 neutralization data generated from seven HIV-1 subtype C serum samples with neutralization breadth that had been tested against a multi-clade panel of 225 pseudoviruses for which envelope sequences were also available. For each sample, between two and four sites were identified that were strongly associated with neutralization sensitivity (2ln(BF) > 6), a subset of which were experimentally confirmed using site-directed mutagenesis.ConclusionsOur results provide strong support for the use of evolutionary models applied to cross-sectional viral neutralization data to identify the epitopes of serum antibodies that confer neutralization breadth.

Prediction of HIV-1 sensitivity to broadly neutralizing antibodies shows a trend towards resistance over time

“…Considering the 15% strongest learnt signals for each classifier, we found that several amino acids ( residues ) of the envelope protein were learnt by the classifiers to influence neutralization resistance or susceptibility, which are also supported by literature [ 39 , 53 ]. In Table 2 we present the learnt signals of the classifiers exemplarily for the bNAbs PG9, PG16, 10-669, 10-1074, PGT121, VRC01, and VRC-PG04 that are supported by previous studies.…”

HIV-1 Envelope Glycoproteins from Diverse Clades Differentiate Antibody Responses and Durability among Vaccinees

“…The antigenicity of these HIV-1 proteins ( Fig. 1A to D and 2A to E ) was determined using samples from human and nonhuman primate vaccine protocols, a panel of HIV-1 monoclonal antibodies (MAbs), and plasma and purified IgG from HIV-1-positive subjects representing multiple HIV-1 clades ( 22 ). Samples from multiple origins were used to provide broad coverage of antibody responses from both infection and vaccination across subtypes.…”

Association Between HIV-1 Coreceptor Usage and Resistance to Broadly Neutralizing Antibodies

“…Unfortunately, Walker et al17 do not provide the env sequences from the test panel, which is why we could not predict coreceptor usage for the test panel they used. However, we could test for an R5-bias on neutralization data from sera of patients of the CAPRISA Acute Infection study with PGT-like neutralization potential 19. For one of the sera, the authors showed computationally and through a mutation study that position 316 was highly relevant for neutralization.…”