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Article: Germline-like predecessors of broadly neutralizing antibodies lack measurable binding to HIV-1 envelope glycoproteins: Implications for evasion of immune responses and design of vaccine immunogens

TitleGermline-like predecessors of broadly neutralizing antibodies lack measurable binding to HIV-1 envelope glycoproteins: Implications for evasion of immune responses and design of vaccine immunogens
Authors
KeywordsAntibody
Escape
Germline
HIV
Immune responses
Vaccine
Issue Date2009
PublisherAcademic Press. The Journal's web site is located at http://www.elsevier.com/wps/find/journaldescription.cws_home/622790/description
Citation
Biochemical And Biophysical Research Communications, 2009, v. 390 n. 3, p. 404-409 How to Cite?
AbstractSeveral human monoclonal antibodies (hmAbs) including b12, 2G12, and 2F5 exhibit relatively potent and broad HIV-1-neutralizing activity. However, their elicitation in vivo by vaccine immunogens based on the HIV-1 envelope glycoprotein (Env) has not been successful. We have hypothesized that HIV-1 has evolved a strategy to reduce or eliminate the immunogenicity of the highly conserved epitopes of such antibodies by using "holes" (absence or very weak binding to these epitopes of germline antibodies that is not sufficient to initiate and/or maintain an efficient immune response) in the human germline B cell receptor (BCR) repertoire. To begin to test this hypothesis we have designed germline-like antibodies corresponding most closely to b12, 2G12, and 2F5 as well as to X5, m44, and m46 which are cross-reactive but with relatively modest neutralizing activity as natively occurring antibodies due to size and/or other effects. The germline-like X5, m44, and m46 bound with relatively high affinity to all tested Envs. In contrast, germline-like b12, 2G12, and 2F5 lacked measurable binding to Envs in an ELISA assay although the corresponding mature antibodies did. These results provide initial evidence that Env structures containing conserved vulnerable epitopes may not initiate humoral responses by binding to germline antibodies. Even if such responses are initiated by very weak binding undetectable in our assay it is likely that they will be outcompeted by responses to structures containing the epitopes of X5, m44, m46, and other antibodies that bind germline BCRs with much higher affinity/avidity. This hypothesis, if further supported by data, could contribute to our understanding of how HIV-1 evades immune responses and offer new concepts for design of effective vaccine immunogens.
Persistent Identifierhttp://hdl.handle.net/10722/65599
ISSN
2014 Impact Factor: 2.297
PubMed Central ID
ISI Accession Number ID
Funding AgencyGrant Number
NIH
National Cancer InstituteN01-CO-12400
Center for Cancer Research
Gates Foundation
Funding Information:

We thank Ruth Ruprecht, Hana Golding, Robert Blumenthal, Christopher Broder, Jorge Flores, Helen Quill, Nancy Miller, Garnett Kelsoe, and Barton Haynes for stimulating discussions and suggestions, Christopher Broder, Gerald Quinnan, Barton Haynes, Dennis Burton, and Tim Fouts for providing reagents, and John Owens for help. This work was supported by the intramural Research Program of the NIH, National Cancer Institute, Center for Cancer Research, by Federal funds from the NIH, National Cancer Institute, under Contract No. N01-CO-12400, and by the Gates Foundation to D.S.D.

References

 

DC FieldValueLanguage
dc.contributor.authorXiao, Xen_HK
dc.contributor.authorChen, Wen_HK
dc.contributor.authorFeng, Yen_HK
dc.contributor.authorZhu, Zen_HK
dc.contributor.authorPrabakaran, Pen_HK
dc.contributor.authorWang, Yen_HK
dc.contributor.authorZhang, MYen_HK
dc.contributor.authorLongo, NSen_HK
dc.contributor.authorDimitrov, DSen_HK
dc.date.accessioned2010-09-03T02:31:36Z-
dc.date.available2010-09-03T02:31:36Z-
dc.date.issued2009en_HK
dc.identifier.citationBiochemical And Biophysical Research Communications, 2009, v. 390 n. 3, p. 404-409en_HK
dc.identifier.issn0006-291Xen_HK
dc.identifier.urihttp://hdl.handle.net/10722/65599-
dc.description.abstractSeveral human monoclonal antibodies (hmAbs) including b12, 2G12, and 2F5 exhibit relatively potent and broad HIV-1-neutralizing activity. However, their elicitation in vivo by vaccine immunogens based on the HIV-1 envelope glycoprotein (Env) has not been successful. We have hypothesized that HIV-1 has evolved a strategy to reduce or eliminate the immunogenicity of the highly conserved epitopes of such antibodies by using "holes" (absence or very weak binding to these epitopes of germline antibodies that is not sufficient to initiate and/or maintain an efficient immune response) in the human germline B cell receptor (BCR) repertoire. To begin to test this hypothesis we have designed germline-like antibodies corresponding most closely to b12, 2G12, and 2F5 as well as to X5, m44, and m46 which are cross-reactive but with relatively modest neutralizing activity as natively occurring antibodies due to size and/or other effects. The germline-like X5, m44, and m46 bound with relatively high affinity to all tested Envs. In contrast, germline-like b12, 2G12, and 2F5 lacked measurable binding to Envs in an ELISA assay although the corresponding mature antibodies did. These results provide initial evidence that Env structures containing conserved vulnerable epitopes may not initiate humoral responses by binding to germline antibodies. Even if such responses are initiated by very weak binding undetectable in our assay it is likely that they will be outcompeted by responses to structures containing the epitopes of X5, m44, m46, and other antibodies that bind germline BCRs with much higher affinity/avidity. This hypothesis, if further supported by data, could contribute to our understanding of how HIV-1 evades immune responses and offer new concepts for design of effective vaccine immunogens.en_HK
dc.languageeng-
dc.publisherAcademic Press. The Journal's web site is located at http://www.elsevier.com/wps/find/journaldescription.cws_home/622790/descriptionen_HK
dc.relation.ispartofBiochemical and Biophysical Research Communicationsen_HK
dc.rightsCreative Commons: Attribution 3.0 Hong Kong License-
dc.subjectAntibodyen_HK
dc.subjectEscapeen_HK
dc.subjectGermlineen_HK
dc.subjectHIVen_HK
dc.subjectImmune responsesen_HK
dc.subjectVaccineen_HK
dc.subject.meshAIDS Vaccines - immunology-
dc.subject.meshAntibodies, Neutralizing - genetics - immunology-
dc.subject.meshAntibody Affinity - genetics - immunology-
dc.subject.meshHIV-1 - immunology-
dc.subject.meshImmune Evasion - immunology-
dc.titleGermline-like predecessors of broadly neutralizing antibodies lack measurable binding to HIV-1 envelope glycoproteins: Implications for evasion of immune responses and design of vaccine immunogensen_HK
dc.typeArticleen_HK
dc.identifier.openurlhttp://library.hku.hk:4550/resserv?sid=HKU:IR&issn=0006-291X&volume=390&issue=3&spage=404&epage=409&date=2009&atitle=Germline-like+predecessors+of+broadly+neutralizing+antibodies+lack+measurable+binding+to+HIV-1+envelope+glycoproteins:+implications+for+evasion+of+immune+responses+and+design+of+vaccine+immunogens-
dc.identifier.emailZhang, MY:zhangmy@hku.hken_HK
dc.identifier.authorityZhang, MY=rp01409en_HK
dc.description.naturepostprint-
dc.identifier.doi10.1016/j.bbrc.2009.09.029en_HK
dc.identifier.pmid19748484en_HK
dc.identifier.pmcidPMC2787893-
dc.identifier.scopuseid_2-s2.0-70449701456en_HK
dc.identifier.hkuros170375-
dc.relation.referenceshttp://www.scopus.com/mlt/select.url?eid=2-s2.0-70449701456&selection=ref&src=s&origin=recordpageen_HK
dc.identifier.volume390en_HK
dc.identifier.issue3en_HK
dc.identifier.spage404en_HK
dc.identifier.epage409en_HK
dc.identifier.isiWOS:000272516700011-
dc.publisher.placeUnited Statesen_HK
dc.identifier.scopusauthoridXiao, X=7402168892en_HK
dc.identifier.scopusauthoridChen, W=8377436000en_HK
dc.identifier.scopusauthoridFeng, Y=7404544509en_HK
dc.identifier.scopusauthoridZhu, Z=11141735600en_HK
dc.identifier.scopusauthoridPrabakaran, P=6603634046en_HK
dc.identifier.scopusauthoridWang, Y=35774687300en_HK
dc.identifier.scopusauthoridZhang, MY=35316639300en_HK
dc.identifier.scopusauthoridLongo, NS=7004663933en_HK
dc.identifier.scopusauthoridDimitrov, DS=7202564539en_HK
dc.identifier.citeulike5796592-

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