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

TitleA single mutation turns a non-binding germline-like predecessor of broadly neutralizing antibody into a binding antibody to HIV-1 envelope glycoproteins
Authors
KeywordsAntibody
Germline
HIV
Immune responses
Vaccine
Issue Date2011
PublisherLandes Bioscience. The Journal's web site is located at http://www.landesbioscience.com/journals/mabs/
Citation
Mabs, 2011, v. 3 n. 4, p. 402-407 How to Cite?
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.
Persistent Identifierhttp://hdl.handle.net/10722/143306
ISSN
2015 Impact Factor: 4.161
PubMed Central ID
ISI Accession Number ID
References

 

DC FieldValueLanguage
dc.contributor.authorYuan, Ten_HK
dc.contributor.authorLi, Jen_HK
dc.contributor.authorZhang, MYen_HK
dc.date.accessioned2011-11-15T06:31:25Z-
dc.date.available2011-11-15T06:31:25Z-
dc.date.issued2011en_HK
dc.identifier.citationMabs, 2011, v. 3 n. 4, p. 402-407en_HK
dc.identifier.issn1942-0862en_HK
dc.identifier.urihttp://hdl.handle.net/10722/143306-
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.en_HK
dc.languageeng-
dc.publisherLandes Bioscience. The Journal's web site is located at http://www.landesbioscience.com/journals/mabs/en_HK
dc.relation.ispartofmAbsen_HK
dc.subjectAntibodyen_HK
dc.subjectGermlineen_HK
dc.subjectHIVen_HK
dc.subjectImmune responsesen_HK
dc.subjectVaccineen_HK
dc.titleA single mutation turns a non-binding germline-like predecessor of broadly neutralizing antibody into a binding antibody to HIV-1 envelope glycoproteinsen_HK
dc.typeArticleen_HK
dc.identifier.openurlhttp://library.hku.hk:4550/resserv?sid=HKU:IR&issn=1942-0862&volume=3&issue=4&spage=402&epage=407&date=2011&atitle=A+single+mutation+turns+a+non-binding+germline-like+predecessor+of+broadly+neutralizing+antibody+into+a+binding+antibody+to+HIV-1+envelope+glycoproteins-
dc.identifier.emailZhang, MY:zhangmy@hku.hken_HK
dc.identifier.authorityZhang, MY=rp01409en_HK
dc.description.naturelink_to_subscribed_fulltext-
dc.identifier.doi10.4161/mabs.3.4.15740en_HK
dc.identifier.pmid21540646en_HK
dc.identifier.pmcidPMC3218537-
dc.identifier.scopuseid_2-s2.0-79960080243en_HK
dc.identifier.hkuros185554-
dc.identifier.hkuros185551en_US
dc.identifier.hkuros185550en_US
dc.relation.referenceshttp://www.scopus.com/mlt/select.url?eid=2-s2.0-79960080243&selection=ref&src=s&origin=recordpageen_HK
dc.identifier.volume3en_HK
dc.identifier.issue4en_HK
dc.identifier.spage402-
dc.identifier.epage407-
dc.identifier.eissn1942-0870-
dc.identifier.isiWOS:000208740500009-
dc.publisher.placeUnited Statesen_HK
dc.identifier.scopusauthoridYuan, T=44161519800en_HK
dc.identifier.scopusauthoridLi, J=44161278900en_HK
dc.identifier.scopusauthoridZhang, MY=35316639300en_HK

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