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dc.contributor.author Gnanakaran, S
dc.contributor.author Daniels, MG
dc.contributor.author Bhattacharya, T
dc.contributor.author Lapedes, AS
dc.contributor.author Sethi, A
dc.contributor.author Li, M
dc.contributor.author Tang, H
dc.contributor.author Greene, K
dc.contributor.author Gao, H
dc.contributor.author Haynes, BF
dc.contributor.author Cohen, MS
dc.contributor.author Shaw, GM
dc.contributor.author Seaman, MS
dc.contributor.author Kumar, A
dc.contributor.author Gao, F
dc.contributor.author Montefiori, DC
dc.contributor.author Korber, B
dc.coverage.spatial United States
dc.date.accessioned 2011-06-21T17:31:13Z
dc.date.issued 2010-10-07
dc.identifier http://www.ncbi.nlm.nih.gov/pubmed/20949103
dc.identifier.citation PLoS Comput Biol, 2010, 6 (10), pp. e1000955 - ?
dc.identifier.uri http://hdl.handle.net/10161/4454
dc.description.abstract A steady increase in knowledge of the molecular and antigenic structure of the gp120 and gp41 HIV-1 envelope glycoproteins (Env) is yielding important new insights for vaccine design, but it has been difficult to translate this information to an immunogen that elicits broadly neutralizing antibodies. To help bridge this gap, we used phylogenetically corrected statistical methods to identify amino acid signature patterns in Envs derived from people who have made potently neutralizing antibodies, with the hypothesis that these Envs may share common features that would be useful for incorporation in a vaccine immunogen. Before attempting this, essentially as a control, we explored the utility of our computational methods for defining signatures of complex neutralization phenotypes by analyzing Env sequences from 251 clonal viruses that were differentially sensitive to neutralization by the well-characterized gp120-specific monoclonal antibody, b12. We identified ten b12-neutralization signatures, including seven either in the b12-binding surface of gp120 or in the V2 region of gp120 that have been previously shown to impact b12 sensitivity. A simple algorithm based on the b12 signature pattern was predictive of b12 sensitivity/resistance in an additional blinded panel of 57 viruses. Upon obtaining these reassuring outcomes, we went on to apply these same computational methods to define signature patterns in Env from HIV-1 infected individuals who had potent, broadly neutralizing responses. We analyzed a checkerboard-style neutralization dataset with sera from 69 HIV-1-infected individuals tested against a panel of 25 different Envs. Distinct clusters of sera with high and low neutralization potencies were identified. Six signature positions in Env sequences obtained from the 69 samples were found to be strongly associated with either the high or low potency responses. Five sites were in the CD4-induced coreceptor binding site of gp120, suggesting an important role for this region in the elicitation of broadly neutralizing antibody responses against HIV-1.
dc.format.extent e1000955 - ?
dc.language ENG
dc.language.iso en_US en_US
dc.relation.ispartof PLoS Comput Biol
dc.relation.isversionof 10.1371/journal.pcbi.1000955
dc.subject Algorithms
dc.subject Amino Acid Sequence
dc.subject Antibodies, Neutralizing
dc.subject Artificial Intelligence
dc.subject Cluster Analysis
dc.subject Computational Biology
dc.subject DNA Mutational Analysis
dc.subject Epitope Mapping
dc.subject Epitopes, T-Lymphocyte
dc.subject HIV Envelope Protein gp120
dc.subject HIV Envelope Protein gp41
dc.subject HIV-1
dc.subject Humans
dc.subject Logistic Models
dc.subject Models, Molecular
dc.subject Mutation
dc.subject Neutralization Tests
dc.subject Phylogeny
dc.subject Sequence Alignment
dc.title Genetic signatures in the envelope glycoproteins of HIV-1 that associate with broadly neutralizing antibodies.
dc.title.alternative en_US
dc.type Journal Article
dc.description.version Version of Record en_US
duke.date.pubdate 2010-10-0 en_US
duke.description.endpage e1000955 en_US
duke.description.issue 10 en_US
duke.description.startpage e1000955 en_US
duke.description.volume 6 en_US
dc.relation.journal Plos Computational Biology en_US
pubs.author-url http://www.ncbi.nlm.nih.gov/pubmed/20949103
pubs.issue 10
pubs.organisational-group /Duke
pubs.organisational-group /Duke/Institutes and Provost's Academic Units
pubs.organisational-group /Duke/Institutes and Provost's Academic Units/University Institutes and Centers
pubs.organisational-group /Duke/Institutes and Provost's Academic Units/University Institutes and Centers/Global Health Institute
pubs.organisational-group /Duke/School of Medicine
pubs.organisational-group /Duke/School of Medicine/Basic Science Departments
pubs.organisational-group /Duke/School of Medicine/Basic Science Departments/Immunology
pubs.organisational-group /Duke/School of Medicine/Clinical Science Departments
pubs.organisational-group /Duke/School of Medicine/Clinical Science Departments/Medicine
pubs.organisational-group /Duke/School of Medicine/Clinical Science Departments/Medicine/Medicine, Duke Human Vaccine Institute
pubs.organisational-group /Duke/School of Medicine/Clinical Science Departments/Medicine/Medicine, Infectious Diseases
pubs.organisational-group /Duke/School of Medicine/Clinical Science Departments/Surgery
pubs.organisational-group /Duke/School of Medicine/Clinical Science Departments/Surgery/Surgery, Surgical Sciences Section for AIDS Research & Development
pubs.organisational-group /Duke/School of Medicine/Institutes and Centers
pubs.organisational-group /Duke/School of Medicine/Institutes and Centers/Duke Cancer Institute
pubs.organisational-group /Duke/School of Medicine/Institutes and Centers/Duke Human Vaccine Institute
pubs.publication-status Published online
pubs.volume 6
dc.identifier.eissn 1553-7358

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