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, M4 5
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
2011 Impact Factor: 9.681
2011 SCImago Journal Rankings: 1.754
DOIhttp://dx.doi.org/10.1073/pnas.102562599
ISI Accession Number IDWOS:000175637300072
ReferencesReferences in Scopus
DC Field
Value
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
2011 Impact Factor: 9.681
2011 SCImago Journal Rankings: 1.754
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
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