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Article: Identification and characterization of a broadly cross-reactive HIV-1 human monoclonal antibody that binds to both gp120 and gp41
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TitleIdentification and characterization of a broadly cross-reactive HIV-1 human monoclonal antibody that binds to both gp120 and gp41
 
AuthorsZhang, M
Yuan, T
Li, J
Borges, AR
Watkins, JD
Guenaga, J
Yang, Z
Wang, Y
Wilson, R
Li, Y
Polonis, VR
Pincus, SH
Ruprecht, RM
Dimitrov, DS
 
Issue Date2012
 
PublisherPublic Library of Science. The Journal's web site is located at http://www.plosone.org/home.action
 
CitationPLoS One, 2012, v. 7 n. 9, e44241 [How to Cite?]
DOI: http://dx.doi.org/10.1371/journal.pone.0044241
 
AbstractIdentification of broadly cross-reactive HIV-1-neutralizing antibodies (bnAbs) may assist vaccine immunogen design. Here we report a novel human monoclonal antibody (mAb), designated m43, which co-targets the gp120 and gp41 subunits of the HIV-1 envelope glycoprotein (Env). M43 bound to recombinant gp140 s from various primary isolates, to membrane-associated Envs on transfected cells and HIV-1 infected cells, as well as to recombinant gp120 s and gp41 fusion intermediate structures containing N-trimer structure, but did not bind to denatured recombinant gp140 s and the CD4 binding site (CD4bs) mutant, gp120 D368R, suggesting that the m43 epitope is conformational and overlaps the CD4bs on gp120 and the N-trimer structure on gp41. M43 neutralized 34% of the HIV-1 primary isolates from different clades and all the SHIVs tested in assays based on infection of peripheral blood mononuclear cells (PBMCs) by replication-competent virus, but was less potent in cell line-based pseudovirus assays. In contrast to CD4, m43 did not induce Env conformational changes upon binding leading to exposure of the coreceptor binding site, enhanced binding of mAbs 2F5 and 4E10 specific for the membrane proximal external region (MPER) of gp41 Envs, or increased gp120 shedding. The overall modest neutralization activity of m43 is likely due to the limited binding of m43 to functional Envs which could be increased by antibody engineering if needed. M43 may represent a new class of bnAbs targeting conformational epitopes overlapping structures on both gp120 and gp41. Its novel epitope and possibly new mechanism(s) of neutralization could helpdesign improved vaccine immunogens and candidate therapeutics.
 
DescriptionOpen Access Journal
Research Article
 
ISSN1932-6203
2013 Impact Factor: 3.534
2013 SCImago Journal Rankings: 1.724
 
DOIhttp://dx.doi.org/10.1371/journal.pone.0044241
 
ISI Accession Number IDWOS:000308748400013
 
DC FieldValue
dc.contributor.authorZhang, M
 
dc.contributor.authorYuan, T
 
dc.contributor.authorLi, J
 
dc.contributor.authorBorges, AR
 
dc.contributor.authorWatkins, JD
 
dc.contributor.authorGuenaga, J
 
dc.contributor.authorYang, Z
 
dc.contributor.authorWang, Y
 
dc.contributor.authorWilson, R
 
dc.contributor.authorLi, Y
 
dc.contributor.authorPolonis, VR
 
dc.contributor.authorPincus, SH
 
dc.contributor.authorRuprecht, RM
 
dc.contributor.authorDimitrov, DS
 
dc.date.accessioned2012-08-16T05:54:47Z
 
dc.date.available2012-08-16T05:54:47Z
 
dc.date.issued2012
 
dc.description.abstractIdentification of broadly cross-reactive HIV-1-neutralizing antibodies (bnAbs) may assist vaccine immunogen design. Here we report a novel human monoclonal antibody (mAb), designated m43, which co-targets the gp120 and gp41 subunits of the HIV-1 envelope glycoprotein (Env). M43 bound to recombinant gp140 s from various primary isolates, to membrane-associated Envs on transfected cells and HIV-1 infected cells, as well as to recombinant gp120 s and gp41 fusion intermediate structures containing N-trimer structure, but did not bind to denatured recombinant gp140 s and the CD4 binding site (CD4bs) mutant, gp120 D368R, suggesting that the m43 epitope is conformational and overlaps the CD4bs on gp120 and the N-trimer structure on gp41. M43 neutralized 34% of the HIV-1 primary isolates from different clades and all the SHIVs tested in assays based on infection of peripheral blood mononuclear cells (PBMCs) by replication-competent virus, but was less potent in cell line-based pseudovirus assays. In contrast to CD4, m43 did not induce Env conformational changes upon binding leading to exposure of the coreceptor binding site, enhanced binding of mAbs 2F5 and 4E10 specific for the membrane proximal external region (MPER) of gp41 Envs, or increased gp120 shedding. The overall modest neutralization activity of m43 is likely due to the limited binding of m43 to functional Envs which could be increased by antibody engineering if needed. M43 may represent a new class of bnAbs targeting conformational epitopes overlapping structures on both gp120 and gp41. Its novel epitope and possibly new mechanism(s) of neutralization could helpdesign improved vaccine immunogens and candidate therapeutics.
 
dc.description.naturelink_to_OA_fulltext
 
dc.descriptionOpen Access Journal
 
dc.descriptionResearch Article
 
dc.identifier.citationPLoS One, 2012, v. 7 n. 9, e44241 [How to Cite?]
DOI: http://dx.doi.org/10.1371/journal.pone.0044241
 
dc.identifier.doihttp://dx.doi.org/10.1371/journal.pone.0044241
 
dc.identifier.hkuros202162
 
dc.identifier.isiWOS:000308748400013
 
dc.identifier.issn1932-6203
2013 Impact Factor: 3.534
2013 SCImago Journal Rankings: 1.724
 
dc.identifier.issue9
 
dc.identifier.pmid22970187
 
dc.identifier.urihttp://hdl.handle.net/10722/159709
 
dc.identifier.volume7
 
dc.languageeng
 
dc.publisherPublic Library of Science. The Journal's web site is located at http://www.plosone.org/home.action
 
dc.publisher.placeUnited States
 
dc.relation.ispartofPLoS One
 
dc.titleIdentification and characterization of a broadly cross-reactive HIV-1 human monoclonal antibody that binds to both gp120 and gp41
 
dc.typeArticle
 
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