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

dc.contributor.authorLacerda, Miguel.
dc.contributor.authorMoore, Penelope L.
dc.contributor.authorNgandu, Nobubelo K.
dc.contributor.authorSeaman, Michael.
dc.contributor.authorGray, Elin Solomonovna.
dc.contributor.authorMurrell, Ben.
dc.contributor.authorKrishnamoorthy, Mohan.
dc.contributor.authorNonyane, Molati.
dc.contributor.authorMadiga, Maphuti C.
dc.contributor.authorWibmer, Constantinos Kurt.
dc.contributor.authorSheward, Daniel J.
dc.contributor.authorBailer, Robert T.
dc.contributor.authorGao, Hongmei.
dc.contributor.authorGreene, Kelli M.
dc.contributor.authorAbdool Karim, Salim Safurdeen.
dc.contributor.authorMascola, John R.
dc.contributor.authorKorber, Bette T. M.
dc.contributor.authorMontefiori, David Charles.
dc.contributor.authorMorris, Lynn.
dc.contributor.authorWilliamson, Carolyn.
dc.contributor.authorSeoighe, Cathal.
dc.date.accessioned2016-09-13T09:07:47Z
dc.date.available2016-09-13T09:07:47Z
dc.date.created2013
dc.date.issued2013
dc.description.abstractBackground: 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.en_US
dc.identifier.citationLacerda, M.; Moore, P.L.; Ngandu, N.K.; Seaman, M.; Gray, E.S.; Murrell, B.; Krishnamoorthy, M.; Nonyane, M.; Madiga, M.; Wibmer, C.K.; Sheward, D.; Bailer, R.T.; Gao, H.; Greene, K.M.; Abdool Karim, S.S.; Mascola, J.R.; Korber, B.T.M.; Montefiori, D.C.; Morris, L.; Williamson, C.; Seoighe, C.; the CAVD-NSDP Consortium. 2013. Identification of broadly neutralizing antibody epitopes in 1 the HIV-1 envelope glycoprotein using evolutionary models. Virology Journal 10(1) p 347.en_US
dc.identifier.urihttp://dx.doi.org/10.1186/1743-422X-10-347en_US
dc.identifier.urihttp://hdl.handle.net/10413/13339
dc.language.isoenen_US
dc.publisherVirology Journalen_US
dc.subject.otherHIV, Antibodies, Neutralization sensitivity, Epitope prediction, Evolutionary modelen_US
dc.titleIdentification of broadly neutralizing antibody epitopes in 1 the HIV-1 envelope glycoprotein using evolutionary models.en_US
dc.typePeer reviewed journal articleen_US

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