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dc.contributor.authorLacerda, Miguel
dc.contributor.authorMoore, Penny L
dc.contributor.authorNgandu, Nobubelo K
dc.contributor.authorSeaman, Michael
dc.contributor.authorGray, Elin S
dc.contributor.authorMurrell, Ben
dc.contributor.authorKrishnamoorthy, Mohan
dc.contributor.authorNonyane, Molati
dc.contributor.authorMadiga, Maphuti
dc.contributor.authorWibmer, Constantinos K
dc.contributor.authorSheward, Daniel
dc.contributor.authorBailer, Robert T
dc.contributor.authorGao, Hongmei
dc.contributor.authorGreene, Kelli M
dc.contributor.authorKarim, Salim S A
dc.contributor.authorMascola, John R
dc.contributor.authorKorber, Bette TM
dc.contributor.authorMontefiori, David C
dc.contributor.authorMorris, Lynn
dc.contributor.authorWilliamson, Carolyn
dc.contributor.authorSeoighe, Cathal
dc.contributor.authorthe CAVD-NSDP Consortium
dc.date.accessioned2014-04-07T11:37:59Z
dc.date.available2014-04-07T11:37:59Z
dc.date.issued2013-12-02
dc.identifier.citationVirology journal. 2013 Dec 02;10(1):347en_GB
dc.identifier.urihttp://dx.doi.org/10.1186/1743-422X-10-347
dc.identifier.urihttp://hdl.handle.net/10147/315461
dc.description.abstractAbstract Background Identification of the epitopes targeted by antibodies that can neutralize diverse HIV-1 strains can provide important clues for the design of a preventative vaccine. Methods We 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. Results We 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. Conclusions Our 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.
dc.language.isoenen
dc.subjectHIV INFECTIONen_GB
dc.subject.otherHUMAN IMMUNODEFICIENCY VIRUSen_GB
dc.titleIdentification of broadly neutralizing antibody epitopes in the HIV-1 envelope glycoprotein using evolutionary modelsen_GB
dc.typeArticleen
dc.identifier.journalVirology journalen_GB
dc.language.rfc3066en
dc.rights.holderMiguel Lacerda et al.; licensee BioMed Central Ltd.
dc.description.statusPeer Reviewed
dc.date.updated2014-04-05T11:18:17Z
refterms.dateFOA2018-08-24T00:20:42Z
html.description.abstractAbstract Background Identification of the epitopes targeted by antibodies that can neutralize diverse HIV-1 strains can provide important clues for the design of a preventative vaccine. Methods We 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. Results We 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. Conclusions Our 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.


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