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Article: Broadly cross-reactive HIV-1-neutralizing human monoclonal Fab selected for binding to gp120-CD4-CCR5 complexes
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TitleBroadly cross-reactive HIV-1-neutralizing human monoclonal Fab selected for binding to gp120-CD4-CCR5 complexes
 
AuthorsMoulard, M5 4
Phogat, SK2
Shu, Y2
Labrijn, AF4
Xiao, D2
Binley, JM4
Zhang, MY2
Sidorov, IA2
Broder, CC6
Robinson, J3
Parren, PWHI1 4
Burton, DR4
Dimitrov, DS2
 
Issue Date2002
 
PublisherNational Academy of Sciences. The Journal's web site is located at http://www.pnas.org
 
CitationProceedings Of The National Academy Of Sciences Of The United States Of America, 2002, v. 99 n. 10, p. 6913-6918 [How to Cite?]
DOI: http://dx.doi.org/10.1073/pnas.102562599
 
AbstractHIV-1 entry into cells involves formation of a complex between gp120 of the viral envelope glycoprotein (Env), a receptor (CD4), and a coreceptor, typically CCR5. Here we provide evidence that purified gp120 JR-FL-CD4-CCR5 complexes exhibit an epitope recognized by a Fab (X5) obtained by selection of a phage display library from a seropositive donor with a relatively high broadly neutralizing serum antibody titer against an immobilized form of the trimolecular complex. X5 bound with high (nM) affinity to a variety of Envs, including primary isolates from different clades and Envs with deleted variable loops (V1, -2, -3). Its binding was significantly increased by CD4 and slightly enhanced by CCR5. X5 inhibited infection of peripheral blood mononuclear cells by a selection of representative HIV-1 primary isolates from clades A, B, C, D, E, F, and G with an efficiency comparable to that of the broadly neutralizing antibody IgG1 b12. Furthermore, X5 inhibited cell fusion mediated by Envs from R5, X4, and R5X4 viruses. Of the five broadly cross-reactive HIV-1 -neutralizing human monoclonal antibodies known to date, X5 is the only one that exhibits increased binding to gp120 complexed with receptors. These findings suggest that X5 could possibly be used as entry inhibitor alone or in combination with other antiretroviral drugs for the treatment of HIV-1-infected individuals, provide evidence for the existence of conserved receptor-inducible gp120 epitopes that can serve as targets for potent broadly cross-reactive neutralizing antibodies in HIV-1-infected patients, and have important conceptual and practical implications for the development of vaccines and inhibitors.
 
ISSN0027-8424
2013 Impact Factor: 9.809
 
DOIhttp://dx.doi.org/10.1073/pnas.102562599
 
ISI Accession Number IDWOS:000175637300072
 
ReferencesReferences in Scopus
 
DC FieldValue
dc.contributor.authorMoulard, M
 
dc.contributor.authorPhogat, SK
 
dc.contributor.authorShu, Y
 
dc.contributor.authorLabrijn, AF
 
dc.contributor.authorXiao, D
 
dc.contributor.authorBinley, JM
 
dc.contributor.authorZhang, MY
 
dc.contributor.authorSidorov, IA
 
dc.contributor.authorBroder, CC
 
dc.contributor.authorRobinson, J
 
dc.contributor.authorParren, PWHI
 
dc.contributor.authorBurton, DR
 
dc.contributor.authorDimitrov, DS
 
dc.date.accessioned2012-08-08T08:49:06Z
 
dc.date.available2012-08-08T08:49:06Z
 
dc.date.issued2002
 
dc.description.abstractHIV-1 entry into cells involves formation of a complex between gp120 of the viral envelope glycoprotein (Env), a receptor (CD4), and a coreceptor, typically CCR5. Here we provide evidence that purified gp120 JR-FL-CD4-CCR5 complexes exhibit an epitope recognized by a Fab (X5) obtained by selection of a phage display library from a seropositive donor with a relatively high broadly neutralizing serum antibody titer against an immobilized form of the trimolecular complex. X5 bound with high (nM) affinity to a variety of Envs, including primary isolates from different clades and Envs with deleted variable loops (V1, -2, -3). Its binding was significantly increased by CD4 and slightly enhanced by CCR5. X5 inhibited infection of peripheral blood mononuclear cells by a selection of representative HIV-1 primary isolates from clades A, B, C, D, E, F, and G with an efficiency comparable to that of the broadly neutralizing antibody IgG1 b12. Furthermore, X5 inhibited cell fusion mediated by Envs from R5, X4, and R5X4 viruses. Of the five broadly cross-reactive HIV-1 -neutralizing human monoclonal antibodies known to date, X5 is the only one that exhibits increased binding to gp120 complexed with receptors. These findings suggest that X5 could possibly be used as entry inhibitor alone or in combination with other antiretroviral drugs for the treatment of HIV-1-infected individuals, provide evidence for the existence of conserved receptor-inducible gp120 epitopes that can serve as targets for potent broadly cross-reactive neutralizing antibodies in HIV-1-infected patients, and have important conceptual and practical implications for the development of vaccines and inhibitors.
 
dc.description.naturelink_to_subscribed_fulltext
 
dc.identifier.citationProceedings Of The National Academy Of Sciences Of The United States Of America, 2002, v. 99 n. 10, p. 6913-6918 [How to Cite?]
DOI: http://dx.doi.org/10.1073/pnas.102562599
 
dc.identifier.citeulike10374358
 
dc.identifier.doihttp://dx.doi.org/10.1073/pnas.102562599
 
dc.identifier.epage6918
 
dc.identifier.isiWOS:000175637300072
 
dc.identifier.issn0027-8424
2013 Impact Factor: 9.809
 
dc.identifier.issue10
 
dc.identifier.pmid11997472
 
dc.identifier.scopuseid_2-s2.0-0037076265
 
dc.identifier.spage6913
 
dc.identifier.urihttp://hdl.handle.net/10722/157346
 
dc.identifier.volume99
 
dc.languageeng
 
dc.publisherNational Academy of Sciences. The Journal's web site is located at http://www.pnas.org
 
dc.publisher.placeUnited States
 
dc.relation.ispartofProceedings of the National Academy of Sciences of the United States of America
 
dc.relation.referencesReferences in Scopus
 
dc.subject.meshAntibodies, Monoclonal - Immunology
 
dc.subject.meshAntibody Affinity
 
dc.subject.meshAntigens, Cd4 - Immunology
 
dc.subject.meshBinding, Competitive
 
dc.subject.meshCell Fusion
 
dc.subject.meshCell Line
 
dc.subject.meshCell Membrane - Immunology
 
dc.subject.meshCross Reactions
 
dc.subject.meshGene Products, Env - Immunology
 
dc.subject.meshHiv Antibodies - Immunology
 
dc.subject.meshHiv Envelope Protein Gp120 - Immunology
 
dc.subject.meshHiv-1 - Immunology - Isolation & Purification
 
dc.subject.meshHumans
 
dc.subject.meshImmunoglobulin Fab Fragments - Immunology
 
dc.subject.meshNeutralization Tests
 
dc.subject.meshPeptide Library
 
dc.subject.meshReceptors, Ccr5 - Immunology
 
dc.subject.meshEnv Gene Products, Human Immunodeficiency Virus
 
dc.titleBroadly cross-reactive HIV-1-neutralizing human monoclonal Fab selected for binding to gp120-CD4-CCR5 complexes
 
dc.typeArticle
 
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Author Affiliations
  1. Genmab
  2. National Cancer Institute at Frederick
  3. Tulane University School of Medicine
  4. Scripps Research Institute
  5. Biocytex
  6. Uniformed Services University of the Health Sciences