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

Hdl Handle:
http://hdl.handle.net/10147/315461
Title:
Identification of broadly neutralizing antibody epitopes in the HIV-1 envelope glycoprotein using evolutionary models
Authors:
Lacerda, Miguel; Moore, Penny L; Ngandu, Nobubelo K; Seaman, Michael; Gray, Elin S; Murrell, Ben; Krishnamoorthy, Mohan; Nonyane, Molati; Madiga, Maphuti; Wibmer, Constantinos K; Sheward, Daniel; Bailer, Robert T; Gao, Hongmei; Greene, Kelli M; Karim, Salim S A; Mascola, John R; Korber, Bette TM; Montefiori, David C; Morris, Lynn; Williamson, Carolyn; Seoighe, Cathal; the CAVD-NSDP Consortium
Citation:
Virology journal. 2013 Dec 02;10(1):347
Journal:
Virology journal
Issue Date:
2-Dec-2013
URI:
http://dx.doi.org/10.1186/1743-422X-10-347; http://hdl.handle.net/10147/315461
Abstract:
Abstract 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.
Item Type:
Article
Language:
en
Keywords:
HIV INFECTION
Local subject classification:
HUMAN IMMUNODEFICIENCY VIRUS

Full metadata record

DC FieldValue Language
dc.contributor.authorLacerda, Miguelen_GB
dc.contributor.authorMoore, Penny Len_GB
dc.contributor.authorNgandu, Nobubelo Ken_GB
dc.contributor.authorSeaman, Michaelen_GB
dc.contributor.authorGray, Elin Sen_GB
dc.contributor.authorMurrell, Benen_GB
dc.contributor.authorKrishnamoorthy, Mohanen_GB
dc.contributor.authorNonyane, Molatien_GB
dc.contributor.authorMadiga, Maphutien_GB
dc.contributor.authorWibmer, Constantinos Ken_GB
dc.contributor.authorSheward, Danielen_GB
dc.contributor.authorBailer, Robert Ten_GB
dc.contributor.authorGao, Hongmeien_GB
dc.contributor.authorGreene, Kelli Men_GB
dc.contributor.authorKarim, Salim S Aen_GB
dc.contributor.authorMascola, John Ren_GB
dc.contributor.authorKorber, Bette TMen_GB
dc.contributor.authorMontefiori, David Cen_GB
dc.contributor.authorMorris, Lynnen_GB
dc.contributor.authorWilliamson, Carolynen_GB
dc.contributor.authorSeoighe, Cathalen_GB
dc.contributor.authorthe CAVD-NSDP Consortiumen_GB
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-
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