Article: A single mutation turns a non-binding germline-like predecessor of broadly neutralizing antibody into a binding antibody to HIV-1 envelope glycoproteins

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TitleA single mutation turns a non-binding germline-like predecessor of broadly neutralizing antibody into a binding antibody to HIV-1 envelope glycoproteins
AuthorsYuan, T1
Li, J1
Zhang, MY1
KeywordsAntibody
Germline
HIV
Immune responses
Vaccine
Issue Date2011
PublisherLandes Bioscience. The Journal's web site is located at http://www.landesbioscience.com/journals/mabs/
CitationMabs, 2011, v. 3 n. 4, p. 402-407 [How to Cite?]
DOI: http://dx.doi.org/10.4161/mabs.3.4.15740
AbstractBroadly neutralizing antibodies (bnAbs) against human immunodeficiency virus (HIV)-1 are rare in natural infection and elicitation of HIV-1 bnAbs has not been achieved by any vaccine candidates. We and others have reported that HIV-1 bnAbs are highly diversified from their germline-like predecessors and the germline-like predecessors of bnAbs lack measurable binding to HIV-1 envelope (Env) glycoproteins, suggesting that Env structures containing the epitopes of bnAbs may not initiate somatic maturation pathway, which may partially explain the rarity of HIV-1 bnAbs. To determine the minimum mutations required for converting non-binding germline-like predecessors to Env-binding antibodies, we started with the bnAb b12 as a prototype and generated six "chimeric" scFv b12 variants by sequentially replacing the heavy chain V-segment (HV), D(J)-segment [HD(J)] in the heavy chain variable region (VH), and the whole light chain variable region (VL) in b12 germline-like predecessor with the mature counterparts. We tested the recombinant scFv variants for binding and neutralizing activities. Results showed that a single point mutation in germline D-segment was enough to convert nonbinding germline-like b12 to an Env-binding antibody. Replacement with either mature HV or mature VL also made the germline-like b12 bind to Env, but none of single segment replacements conferred neutralization ability to the germline antibody. Mature VL in combination with mature HD(J) or mature HV, or both conferred increasing neutralization activity to the germline antibody. However, hybrid scFv, mature VH/germline VL, did not neutralize HIV-1, suggesting the importance of mature VL in neutralizing the virus. These results may have implications for vaccine development. © 2011 Landes Bioscience.
ISSN1942-0862
2011 Impact Factor: 3.174
DOIhttp://dx.doi.org/10.4161/mabs.3.4.15740
PubMed Central IDPMC3218537
ReferencesReferences in Scopus
DC Field
Value
dc.contributor.authorYuan, T
dc.contributor.authorLi, J
dc.contributor.authorZhang, MY
dc.date.accessioned2011-11-15T06:31:25Z
dc.date.available2011-11-15T06:31:25Z
dc.date.issued2011
dc.description.abstractBroadly neutralizing antibodies (bnAbs) against human immunodeficiency virus (HIV)-1 are rare in natural infection and elicitation of HIV-1 bnAbs has not been achieved by any vaccine candidates. We and others have reported that HIV-1 bnAbs are highly diversified from their germline-like predecessors and the germline-like predecessors of bnAbs lack measurable binding to HIV-1 envelope (Env) glycoproteins, suggesting that Env structures containing the epitopes of bnAbs may not initiate somatic maturation pathway, which may partially explain the rarity of HIV-1 bnAbs. To determine the minimum mutations required for converting non-binding germline-like predecessors to Env-binding antibodies, we started with the bnAb b12 as a prototype and generated six "chimeric" scFv b12 variants by sequentially replacing the heavy chain V-segment (HV), D(J)-segment [HD(J)] in the heavy chain variable region (VH), and the whole light chain variable region (VL) in b12 germline-like predecessor with the mature counterparts. We tested the recombinant scFv variants for binding and neutralizing activities. Results showed that a single point mutation in germline D-segment was enough to convert nonbinding germline-like b12 to an Env-binding antibody. Replacement with either mature HV or mature VL also made the germline-like b12 bind to Env, but none of single segment replacements conferred neutralization ability to the germline antibody. Mature VL in combination with mature HD(J) or mature HV, or both conferred increasing neutralization activity to the germline antibody. However, hybrid scFv, mature VH/germline VL, did not neutralize HIV-1, suggesting the importance of mature VL in neutralizing the virus. These results may have implications for vaccine development. © 2011 Landes Bioscience.
dc.description.natureLink_to_subscribed_fulltext
dc.identifier.citationMabs, 2011, v. 3 n. 4, p. 402-407 [How to Cite?]
DOI: http://dx.doi.org/10.4161/mabs.3.4.15740
dc.identifier.doihttp://dx.doi.org/10.4161/mabs.3.4.15740
dc.identifier.epage407
dc.identifier.hkuros185554
dc.identifier.hkuros185551
dc.identifier.hkuros185550
dc.identifier.issn1942-0862
2011 Impact Factor: 3.174
dc.identifier.issue4
dc.identifier.openurl
dc.identifier.pmcidPMC3218537
dc.identifier.pmid21540646
dc.identifier.scopuseid_2-s2.0-79960080243
dc.identifier.spage402
dc.identifier.urihttp://hdl.handle.net/10722/143306
dc.identifier.volume3
dc.languageeng
dc.publisherLandes Bioscience. The Journal's web site is located at http://www.landesbioscience.com/journals/mabs/
dc.publisher.placeUnited States
dc.relation.ispartofmAbs
dc.relation.referencesReferences in Scopus
dc.subjectAntibody
dc.subjectGermline
dc.subjectHIV
dc.subjectImmune responses
dc.subjectVaccine
dc.titleA single mutation turns a non-binding germline-like predecessor of broadly neutralizing antibody into a binding antibody to HIV-1 envelope glycoproteins
dc.typeArticle
Author Affiliations
  1. The University of Hong Kong