Dataset Information

A Prominent Site of Antibody Vulnerability on HIV Envelope Incorporates a Motif Associated with CCR5 Binding and Its Camouflaging Glycans.

ABSTRACT: The dense patch of high-mannose-type glycans surrounding the N332 glycan on the HIV envelope glycoprotein (Env) is targeted by multiple broadly neutralizing antibodies (bnAbs). This region is relatively conserved, implying functional importance, the origins of which are not well understood. Here we describe the isolation of new bnAbs targeting this region. Examination of these and previously described antibodies to Env revealed that four different bnAb families targeted the (324)GDIR(327) peptide stretch at the base of the gp120 V3 loop and its nearby glycans. We found that this peptide stretch constitutes part of the CCR5 co-receptor binding site, with the high-mannose patch glycans serving to camouflage it from most antibodies. GDIR-glycan bnAbs, in contrast, bound both (324)GDIR(327) peptide residues and high-mannose patch glycans, which enabled broad reactivity against diverse HIV isolates. Thus, as for the CD4 binding site, bnAb effectiveness relies on circumventing the defenses of a critical functional region on Env.

SUBMITTER: Sok D

PROVIDER: S-EPMC4990068 | biostudies-literature | 2016 Jul

REPOSITORIES: biostudies-literature

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A Prominent Site of Antibody Vulnerability on HIV Envelope Incorporates a Motif Associated with CCR5 Binding and Its Camouflaging Glycans.

Sok Devin D Pauthner Matthias M Briney Bryan B Lee Jeong Hyun JH Saye-Francisco Karen L KL Hsueh Jessica J Ramos Alejandra A Le Khoa M KM Jones Meaghan M Jardine Joseph G JG Bastidas Raiza R Sarkar Anita A Liang Chi-Hui CH Shivatare Sachin S SS Wu Chung-Yi CY Schief William R WR Wong Chi-Huey CH Wilson Ian A IA Ward Andrew B AB Zhu Jiang J Poignard Pascal P Burton Dennis R DR

Immunity 20160701 1

The dense patch of high-mannose-type glycans surrounding the N332 glycan on the HIV envelope glycoprotein (Env) is targeted by multiple broadly neutralizing antibodies (bnAbs). This region is relatively conserved, implying functional importance, the origins of which are not well understood. Here we describe the isolation of new bnAbs targeting this region. Examination of these and previously described antibodies to Env revealed that four different bnAb families targeted the (324)GDIR(327) peptid ...[more]

PMID: 27438765

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Project description:A central problem in the bioinformatics of gene regulation is to find the binding sites for regulatory proteins. One of the most promising approaches toward identifying these short and fuzzy sequence patterns is the comparative analysis of orthologous intergenic regions of related species. This analysis is complicated by various factors. First, one needs to take the phylogenetic relationship between the species into account in order to distinguish conservation that is due to the occurrence of functional sites from spurious conservation that is due to evolutionary proximity. Second, one has to deal with the complexities of multiple alignments of orthologous intergenic regions, and one has to consider the possibility that functional sites may occur outside of conserved segments. Here we present a new motif sampling algorithm, PhyloGibbs, that runs on arbitrary collections of multiple local sequence alignments of orthologous sequences. The algorithm searches over all ways in which an arbitrary number of binding sites for an arbitrary number of transcription factors (TFs) can be assigned to the multiple sequence alignments. These binding site configurations are scored by a Bayesian probabilistic model that treats aligned sequences by a model for the evolution of binding sites and "background" intergenic DNA. This model takes the phylogenetic relationship between the species in the alignment explicitly into account. The algorithm uses simulated annealing and Monte Carlo Markov-chain sampling to rigorously assign posterior probabilities to all the binding sites that it reports. In tests on synthetic data and real data from five Saccharomyces species our algorithm performs significantly better than four other motif-finding algorithms, including algorithms that also take phylogeny into account. Our results also show that, in contrast to the other algorithms, PhyloGibbs can make realistic estimates of the reliability of its predictions. Our tests suggest that, running on the five-species multiple alignment of a single gene's upstream region, PhyloGibbs on average recovers over 50% of all binding sites in S. cerevisiae at a specificity of about 50%, and 33% of all binding sites at a specificity of about 85%. We also tested PhyloGibbs on collections of multiple alignments of intergenic regions that were recently annotated, based on ChIP-on-chip data, to contain binding sites for the same TF. We compared PhyloGibbs's results with the previous analysis of these data using six other motif-finding algorithms. For 16 of 21 TFs for which all other motif-finding methods failed to find a significant motif, PhyloGibbs did recover a motif that matches the literature consensus. In 11 cases where there was disagreement in the results we compiled lists of known target genes from the literature, and found that running PhyloGibbs on their regulatory regions yielded a binding motif matching the literature consensus in all but one of the cases. Interestingly, these literature gene lists had little overlap with the targets annotated based on the ChIP-on-chip data. The PhyloGibbs code can be downloaded from http://www.biozentrum.unibas.ch/~nimwegen/cgi-bin/phylogibbs.cgi or http://www.imsc.res.in/~rsidd/phylogibbs. The full set of predicted sites from our tests on yeast are available at http://www.swissregulon.unibas.ch.

Dataset Information

A Prominent Site of Antibody Vulnerability on HIV Envelope Incorporates a Motif Associated with CCR5 Binding and Its Camouflaging Glycans.

Publications

A Prominent Site of Antibody Vulnerability on HIV Envelope Incorporates a Motif Associated with CCR5 Binding and Its Camouflaging Glycans.

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