title: Identification of broadly neutralizing antibody epitopes in the HIV-1 envelope glycoprotein using evolutionary models.
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.
authors.forename: Miguel
authors.initials: M
authors.lastname: Lacerda
authors.forename: Penny L
authors.initials: PL
authors.lastname: Moore
authors.forename: Nobubelo K
authors.initials: NK
authors.lastname: Ngandu
authors.forename: Michael
authors.initials: M
authors.lastname: Seaman
authors.forename: Elin S
authors.initials: ES
authors.lastname: Gray
authors.forename: Ben
authors.initials: B
authors.lastname: Murrell
authors.forename: Mohan
authors.initials: M
authors.lastname: Krishnamoorthy
authors.forename: Molati
authors.initials: M
authors.lastname: Nonyane
authors.forename: Maphuti
authors.initials: M
authors.lastname: Madiga
authors.forename: Constantinos Kurt
authors.initials: CK
authors.lastname: Wibmer
authors.forename: Daniel
authors.initials: D
authors.lastname: Sheward
authors.forename: Robert T
authors.initials: RT
authors.lastname: Bailer
authors.forename: Hongmei
authors.initials: H
authors.lastname: Gao
authors.forename: Kelli M
authors.initials: KM
authors.lastname: Greene
authors.forename: Salim S Abdool
authors.initials: SS
authors.lastname: Karim
authors.forename: John R
authors.initials: JR
authors.lastname: Mascola
authors.forename: Bette T M
authors.initials: BT
authors.lastname: Korber
authors.forename: David C
authors.initials: DC
authors.lastname: Montefiori
authors.forename: Lynn
authors.initials: L
authors.lastname: Morris
authors.forename: Carolyn
authors.initials: C
authors.lastname: Williamson
authors.affiliation: School of Mathematics, Statistics and Applied Mathematics, National University of Ireland Galway, Galway, Ireland. cathal.seoighe@nuigalway.ie.
authors.forename: Cathal
authors.initials: C
authors.lastname: Seoighe
mesh_terms: D057134:Antibodies, Neutralizing / Q000276:immunology*; D019295:Computational Biology / Q000379:methods; D003429:Cross Reactions; D000939:Epitopes / Q000235:genetics / Q000276:immunology*; D015483:HIV Antibodies / Q000276:immunology*; D015497:HIV-1 / Q000235:genetics / Q000276:immunology*; D054299:env Gene Products, Human Immunodeficiency Virus / Q000235:genetics / Q000276:immunology*
chemical_list: D057134:Antibodies, Neutralizing; D000939:Epitopes; D015483:HIV Antibodies; D054299:env Gene Products, Human Immunodeficiency Virus