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Publication Details
AFRICAN RESEARCH NEXUS
SHINING A SPOTLIGHT ON AFRICAN RESEARCH
Identification of broadly neutralizing antibody epitopes in the HIV-1 envelope glycoprotein using evolutionary models
Virology Journal, Volume 10, Article 347, Year 2013
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Description
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 ID§ssub§50§esub§ 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. © 2013 Lacerda et al.; licensee BioMed Central Ltd.
Available Materials
https://efashare.b-cdn.net/share/pmc/articles/PMC4220805/bin/1743-422X-10-347-S1.pdf
https://efashare.b-cdn.net/share/pmc/articles/PMC4220805/bin/1743-422X-10-347-S2.doc
https://efashare.b-cdn.net/share/pmc/articles/PMC4220805/bin/1743-422X-10-347-S3.fas
https://efashare.b-cdn.net/share/pmc/articles/PMC4220805/bin/1743-422X-10-347-S4.xls
Authors & Co-Authors
Lacerda, Miguel
Ireland, Galway
University of Galway
South Africa, Cape Town
Faculty of Health Sciences
Moore, Penny L.
South Africa, Johannesburg
National Institute for Communicable Diseases
South Africa, Johannesburg
School of Pathology
Ngandu, Nobubelo Kwanele
South Africa, Cape Town
Faculty of Health Sciences
Seaman, Michael S.
United States, Boston
Beth Israel Deaconess Medical Center
Gray, Elin Solomonovna
South Africa, Johannesburg
National Institute for Communicable Diseases
Murrell, Ben
South Africa, Tygerberg
South African Medical Research Council
South Africa, Stellenbosch
Stellenbosch University
Krishnamoorthy, Mohan
United States, Los Alamos
Los Alamos National Laboratory
Nonyane, Molati
South Africa, Johannesburg
National Institute for Communicable Diseases
Madiga, Maphuti Carol
South Africa, Johannesburg
National Institute for Communicable Diseases
Wibmer, Constantinos Kurt
South Africa, Johannesburg
National Institute for Communicable Diseases
Sheward, Daniel J.
South Africa, Cape Town
Faculty of Health Sciences
Bailer, Robert T.
United States, Bethesda
National Institute of Allergy and Infectious Diseases Niaid
Gao, Hongmei
United States, Durham
Duke University Medical Center
Greene, Kelli M.
United States, Durham
Duke University Medical Center
Abdool Karim, Salim S.
South Africa, Congella
Centre for the Aids Programme of Research in South Africa
United States, New York
Columbia University
Mascola, John R.
United States, Bethesda
National Institute of Allergy and Infectious Diseases Niaid
Korber, Bette T.
United States, Los Alamos
Los Alamos National Laboratory
United States, Santa fe
Santa fe Institute
Montefiori, David Charles
United States, Durham
Duke University Medical Center
Morris, Lynn
South Africa, Johannesburg
National Institute for Communicable Diseases
South Africa, Johannesburg
School of Pathology
Williamson, Carolyn
South Africa, Cape Town
Faculty of Health Sciences
Seoighe, Cathal
Ireland, Galway
University of Galway
Statistics
Citations: 21
Authors: 21
Affiliations: 14
Identifiers
Doi:
10.1186/1743-422X-10-347
e-ISSN:
1743422X
Research Areas
Infectious Diseases
Study Design
Cross Sectional Study