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Article: Monoclonal antibody m18 paratope leading to dual receptor antagonism of HIV-1 gp120

TitleMonoclonal antibody m18 paratope leading to dual receptor antagonism of HIV-1 gp120
Authors
Issue Date2011
PublisherAmerican Chemical Society. The Journal's web site is located at http://pubs.acs.org/biochemistry
Citation
Biochemistry, 2011, v. 50 n. 14, p. 2769-2779 How to Cite?
AbstractWe sought to identify sequences in the monoclonal antibody m18 complementarity determining regions (CDRs) that are responsible for its interaction with HIV-1 gp120 and inhibition of the envelope receptor binding sites. In the accompanying paper (DOI 10.1021/bi101160r), we reported that m18 inhibits CD4 binding through a nonactivating mechanism that, at the same time, induces conformational effects leading to inhibition of the coreceptor site. Here, we sought to define the structural elements in m18 responsible for these actions. Direct binding and competition analyses using surface plasmon resonance showed that YU-2 gp120 binding is stabilized by a broad paratope of residues in the m18 CDRs. Additionally, several m18 residues were identified for which mutants retained high affinity for gp120 but had suppressed CD4 and 17b inhibition activities. A subset of these mutants did, however, neutralize HXBc2 viral infection. The results obtained in this work demonstrate that the combined m18 paratope contains subsets of residues that are differentially important for the binding and inhibition functions of the m18 neutralizing antibody. The data also add to prior observations that high-affinity antibodies that do not inhibit monomeric gp120 receptor site interactions may still exhibit significant antiviral activity.(Figure Presented) © 2011 American Chemical Society.
Persistent Identifierhttp://hdl.handle.net/10722/157630
ISSN
2015 Impact Factor: 2.876
2015 SCImago Journal Rankings: 1.769
ISI Accession Number ID
Funding AgencyGrant Number
National Institutes of HealthP01 GM 56550
CHAVI UI9AI067854-04
NIH, National Cancer Institute, Center for Cancer Research
Funding Information:

This research was supported by National Institutes of Health Grants P01 GM 56550 and CHAVI UI9AI067854-04 and by the Intramural Research Program of the NIH, National Cancer Institute, Center for Cancer Research.

References

 

DC FieldValueLanguage
dc.contributor.authorGift, SKen_US
dc.contributor.authorMcfadden, Ken_US
dc.contributor.authorZentner, IJen_US
dc.contributor.authorRajagopal, Sen_US
dc.contributor.authorZhang, MYen_US
dc.contributor.authorDimitrov, DSen_US
dc.contributor.authorChaiken, IMen_US
dc.date.accessioned2012-08-08T08:51:49Z-
dc.date.available2012-08-08T08:51:49Z-
dc.date.issued2011en_US
dc.identifier.citationBiochemistry, 2011, v. 50 n. 14, p. 2769-2779en_US
dc.identifier.issn0006-2960en_US
dc.identifier.urihttp://hdl.handle.net/10722/157630-
dc.description.abstractWe sought to identify sequences in the monoclonal antibody m18 complementarity determining regions (CDRs) that are responsible for its interaction with HIV-1 gp120 and inhibition of the envelope receptor binding sites. In the accompanying paper (DOI 10.1021/bi101160r), we reported that m18 inhibits CD4 binding through a nonactivating mechanism that, at the same time, induces conformational effects leading to inhibition of the coreceptor site. Here, we sought to define the structural elements in m18 responsible for these actions. Direct binding and competition analyses using surface plasmon resonance showed that YU-2 gp120 binding is stabilized by a broad paratope of residues in the m18 CDRs. Additionally, several m18 residues were identified for which mutants retained high affinity for gp120 but had suppressed CD4 and 17b inhibition activities. A subset of these mutants did, however, neutralize HXBc2 viral infection. The results obtained in this work demonstrate that the combined m18 paratope contains subsets of residues that are differentially important for the binding and inhibition functions of the m18 neutralizing antibody. The data also add to prior observations that high-affinity antibodies that do not inhibit monomeric gp120 receptor site interactions may still exhibit significant antiviral activity.(Figure Presented) © 2011 American Chemical Society.en_US
dc.languageengen_US
dc.publisherAmerican Chemical Society. The Journal's web site is located at http://pubs.acs.org/biochemistryen_US
dc.relation.ispartofBiochemistryen_US
dc.subject.meshAntibodies, Monoclonal - Chemistry - Genetics - Metabolismen_US
dc.subject.meshAntibodies, Neutralizing - Chemistry - Genetics - Metabolismen_US
dc.subject.meshAntigens, Cd4 - Immunology - Metabolismen_US
dc.subject.meshBinding Sites - Drug Effectsen_US
dc.subject.meshBinding, Competitiveen_US
dc.subject.meshComplementarity Determining Regions - Chemistry - Genetics - Metabolismen_US
dc.subject.meshEpitopes - Chemistry - Genetics - Metabolismen_US
dc.subject.meshHiv Antibodies - Chemistry - Genetics - Metabolismen_US
dc.subject.meshHiv Envelope Protein Gp120 - Metabolismen_US
dc.subject.meshHiv-1 - Immunology - Metabolismen_US
dc.subject.meshHumansen_US
dc.subject.meshImmunoglobulin Fab Fragments - Chemistry - Immunology - Metabolismen_US
dc.subject.meshModels, Molecularen_US
dc.subject.meshMutationen_US
dc.subject.meshProtein Bindingen_US
dc.subject.meshProtein Conformationen_US
dc.titleMonoclonal antibody m18 paratope leading to dual receptor antagonism of HIV-1 gp120en_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.doi10.1021/bi101161jen_US
dc.identifier.pmid21417283-
dc.identifier.scopuseid_2-s2.0-79953727282en_US
dc.identifier.hkuros185548-
dc.relation.referenceshttp://www.scopus.com/mlt/select.url?eid=2-s2.0-79953727282&selection=ref&src=s&origin=recordpageen_US
dc.identifier.volume50en_US
dc.identifier.issue14en_US
dc.identifier.spage2769en_US
dc.identifier.epage2779en_US
dc.identifier.isiWOS:000289029200008-
dc.publisher.placeUnited Statesen_US
dc.identifier.scopusauthoridGift, SK=47860915200en_US
dc.identifier.scopusauthoridMcFadden, K=7003822811en_US
dc.identifier.scopusauthoridZentner, IJ=24170380800en_US
dc.identifier.scopusauthoridRajagopal, S=37034779200en_US
dc.identifier.scopusauthoridZhang, MY=35316639300en_US
dc.identifier.scopusauthoridDimitrov, DS=7202564539en_US
dc.identifier.scopusauthoridChaiken, IM=7005080392en_US

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