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

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dc.contributor.authorLacerda, Miguelen_ZA
dc.contributor.authorMoore, Pennyen_ZA
dc.contributor.authorNgandu, Nobubeloen_ZA
dc.contributor.authorSeaman, Michaelen_ZA
dc.contributor.authorGray, Elinen_ZA
dc.contributor.authorMurrell, Benen_ZA
dc.contributor.authorKrishnamoorthy, Mohanen_ZA
dc.contributor.authorNonyane, Molatien_ZA
dc.contributor.authorMadiga, Maphutien_ZA
dc.contributor.authorWibmer, Constantinosen_ZA
dc.contributor.authorSheward, Danielen_ZA
dc.contributor.authorBailer, Roberten_ZA
dc.contributor.authorGao, Hongmeien_ZA
dc.contributor.authorGreene, Kellien_ZA
dc.contributor.authorKarim, Salim Sen_ZA
dc.contributor.authorMen_ZA
dc.date.accessioned2015-11-04T11:57:48Z
dc.date.available2015-11-04T11:57:48Z
dc.date.issued2013en_ZA
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_ZA
dc.identifier.apacitationLacerda, M., Moore, P., Ngandu, N., Seaman, M., Gray, E., Murrell, B., ... (2013). Identification of broadly neutralizing antibody epitopes in the HIV-1 envelope glycoprotein using evolutionary models. <i>Virology Journal</i>, http://hdl.handle.net/11427/14683en_ZA
dc.identifier.chicagocitationLacerda, Miguel, Penny Moore, Nobubelo Ngandu, Michael Seaman, Elin Gray, Ben Murrell, Mohan Krishnamoorthy, et al "Identification of broadly neutralizing antibody epitopes in the HIV-1 envelope glycoprotein using evolutionary models." <i>Virology Journal</i> (2013) http://hdl.handle.net/11427/14683en_ZA
dc.identifier.citationLacerda, M., Moore, P. L., Ngandu, N. K., Seaman, M., Gray, E. S., Murrell, B., ... & CAVD-NSDP Consortium. (2013). Identification of broadly neutralizing antibody epitopes in the HIV-1 envelope glycoprotein using evolutionary models. Virol J, 10, 347.en_ZA
dc.identifier.ris TY - Journal Article AU - Lacerda, Miguel AU - Moore, Penny AU - Ngandu, Nobubelo AU - Seaman, Michael AU - Gray, Elin AU - Murrell, Ben AU - Krishnamoorthy, Mohan AU - Nonyane, Molati AU - Madiga, Maphuti AU - Wibmer, Constantinos AU - Sheward, Daniel AU - Bailer, Robert AU - Gao, Hongmei AU - Greene, Kelli AU - Karim, Salim S AU - M AB - 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. DA - 2013 DB - OpenUCT DO - 10.1186/1743-422X-10-347 DP - University of Cape Town J1 - Virology Journal LK - https://open.uct.ac.za PB - University of Cape Town PY - 2013 T1 - Identification of broadly neutralizing antibody epitopes in the HIV-1 envelope glycoprotein using evolutionary models TI - Identification of broadly neutralizing antibody epitopes in the HIV-1 envelope glycoprotein using evolutionary models UR - http://hdl.handle.net/11427/14683 ER - en_ZA
dc.identifier.urihttp://hdl.handle.net/11427/14683
dc.identifier.urihttp://dx.doi.org/10.1186/1743-422X-10-347
dc.identifier.vancouvercitationLacerda M, Moore P, Ngandu N, Seaman M, Gray E, Murrell B, et al. Identification of broadly neutralizing antibody epitopes in the HIV-1 envelope glycoprotein using evolutionary models. Virology Journal. 2013; http://hdl.handle.net/11427/14683.en_ZA
dc.language.isoengen_ZA
dc.publisherBioMed Central Ltden_ZA
dc.publisher.departmentDepartment of Statistical Sciencesen_ZA
dc.publisher.facultyFaculty of Scienceen_ZA
dc.publisher.institutionUniversity of Cape Town
dc.rightsThis is an Open Access article distributed under the terms of the Creative Commons Attribution Licenseen_ZA
dc.rights.holder2013 Lacerda et al.; licensee BioMed Central Ltd.en_ZA
dc.rights.urihttp://creativecommons.org/licenses/by/2.0en_ZA
dc.sourceVirology Journalen_ZA
dc.source.urihttp://www.virologyj.com/en_ZA
dc.subject.otherHIVen_ZA
dc.subject.otherAntibodiesen_ZA
dc.subject.otherNeutralization sensitivityen_ZA
dc.subject.otherEpitope predictionen_ZA
dc.subject.otherEvolutionary modelen_ZA
dc.titleIdentification of broadly neutralizing antibody epitopes in the HIV-1 envelope glycoprotein using evolutionary modelsen_ZA
dc.typeJournal Articleen_ZA
uct.type.filetypeText
uct.type.filetypeImage
uct.type.publicationResearchen_ZA
uct.type.resourceArticleen_ZA
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