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Article: Broadly cross-reactive HIV-1-neutralizing human monoclonal Fab selected for binding to gp120-CD4-CCR5 complexes

TitleBroadly cross-reactive HIV-1-neutralizing human monoclonal Fab selected for binding to gp120-CD4-CCR5 complexes
Authors
Issue Date2002
PublisherNational Academy of Sciences. The Journal's web site is located at http://www.pnas.org
Citation
Proceedings Of The National Academy Of Sciences Of The United States Of America, 2002, v. 99 n. 10, p. 6913-6918 How to Cite?
Abstract
HIV-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.
Persistent Identifierhttp://hdl.handle.net/10722/157346
ISSN
2013 Impact Factor: 9.809
ISI Accession Number ID
References

 

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
DC FieldValueLanguage
dc.contributor.authorMoulard, Men_US
dc.contributor.authorPhogat, SKen_US
dc.contributor.authorShu, Yen_US
dc.contributor.authorLabrijn, AFen_US
dc.contributor.authorXiao, Den_US
dc.contributor.authorBinley, JMen_US
dc.contributor.authorZhang, MYen_US
dc.contributor.authorSidorov, IAen_US
dc.contributor.authorBroder, CCen_US
dc.contributor.authorRobinson, Jen_US
dc.contributor.authorParren, PWHIen_US
dc.contributor.authorBurton, DRen_US
dc.contributor.authorDimitrov, DSen_US
dc.date.accessioned2012-08-08T08:49:06Z-
dc.date.available2012-08-08T08:49:06Z-
dc.date.issued2002en_US
dc.identifier.citationProceedings Of The National Academy Of Sciences Of The United States Of America, 2002, v. 99 n. 10, p. 6913-6918en_US
dc.identifier.issn0027-8424en_US
dc.identifier.urihttp://hdl.handle.net/10722/157346-
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.en_US
dc.languageengen_US
dc.publisherNational Academy of Sciences. The Journal's web site is located at http://www.pnas.orgen_US
dc.relation.ispartofProceedings of the National Academy of Sciences of the United States of Americaen_US
dc.subject.meshAntibodies, Monoclonal - Immunologyen_US
dc.subject.meshAntibody Affinityen_US
dc.subject.meshAntigens, Cd4 - Immunologyen_US
dc.subject.meshBinding, Competitiveen_US
dc.subject.meshCell Fusionen_US
dc.subject.meshCell Lineen_US
dc.subject.meshCell Membrane - Immunologyen_US
dc.subject.meshCross Reactionsen_US
dc.subject.meshGene Products, Env - Immunologyen_US
dc.subject.meshHiv Antibodies - Immunologyen_US
dc.subject.meshHiv Envelope Protein Gp120 - Immunologyen_US
dc.subject.meshHiv-1 - Immunology - Isolation & Purificationen_US
dc.subject.meshHumansen_US
dc.subject.meshImmunoglobulin Fab Fragments - Immunologyen_US
dc.subject.meshNeutralization Testsen_US
dc.subject.meshPeptide Libraryen_US
dc.subject.meshReceptors, Ccr5 - Immunologyen_US
dc.subject.meshEnv Gene Products, Human Immunodeficiency Virusen_US
dc.titleBroadly cross-reactive HIV-1-neutralizing human monoclonal Fab selected for binding to gp120-CD4-CCR5 complexesen_US
dc.typeArticleen_US
dc.identifier.emailZhang, MY:zhangmy@hku.hken_US
dc.identifier.authorityZhang, MY=rp01409en_US
dc.description.naturelink_to_subscribed_fulltexten_US
dc.identifier.doi10.1073/pnas.102562599en_US
dc.identifier.pmid11997472en_US
dc.identifier.scopuseid_2-s2.0-0037076265en_US
dc.relation.referenceshttp://www.scopus.com/mlt/select.url?eid=2-s2.0-0037076265&selection=ref&src=s&origin=recordpageen_US
dc.identifier.volume99en_US
dc.identifier.issue10en_US
dc.identifier.spage6913en_US
dc.identifier.epage6918en_US
dc.identifier.isiWOS:000175637300072-
dc.publisher.placeUnited Statesen_US
dc.identifier.scopusauthoridMoulard, M=6701530177en_US
dc.identifier.scopusauthoridPhogat, SK=6602665528en_US
dc.identifier.scopusauthoridShu, Y=7103239429en_US
dc.identifier.scopusauthoridLabrijn, AF=6507797385en_US
dc.identifier.scopusauthoridXiao, D=37110469400en_US
dc.identifier.scopusauthoridBinley, JM=6603861952en_US
dc.identifier.scopusauthoridZhang, MY=35316639300en_US
dc.identifier.scopusauthoridSidorov, IA=7005186545en_US
dc.identifier.scopusauthoridBroder, CC=7004376461en_US
dc.identifier.scopusauthoridRobinson, J=35418328400en_US
dc.identifier.scopusauthoridParren, PWHI=7004044140en_US
dc.identifier.scopusauthoridBurton, DR=7401577043en_US
dc.identifier.scopusauthoridDimitrov, DS=7202564539en_US
dc.identifier.citeulike10374358-

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