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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
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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
 
AuthorsXiao, X1
Chen, W1
Feng, Y1
Zhu, Z1 2
Prabakaran, P1
Wang, Y1 2
Zhang, MY1 2
Longo, NS3
Dimitrov, DS1
 
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
 
CitationBiochemical And Biophysical Research Communications, 2009, v. 390 n. 3, p. 404-409 [How to Cite?]
DOI: http://dx.doi.org/10.1016/j.bbrc.2009.09.029
 
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.
 
ISSN0006-291X
2013 Impact Factor: 2.281
 
DOIhttp://dx.doi.org/10.1016/j.bbrc.2009.09.029
 
PubMed Central IDPMC2787893
 
ISI Accession Number IDWOS:000272516700011
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.

 
ReferencesReferences in Scopus
 
DC FieldValue
dc.contributor.authorXiao, X
 
dc.contributor.authorChen, W
 
dc.contributor.authorFeng, Y
 
dc.contributor.authorZhu, Z
 
dc.contributor.authorPrabakaran, P
 
dc.contributor.authorWang, Y
 
dc.contributor.authorZhang, MY
 
dc.contributor.authorLongo, NS
 
dc.contributor.authorDimitrov, DS
 
dc.date.accessioned2010-09-03T02:31:36Z
 
dc.date.available2010-09-03T02:31:36Z
 
dc.date.issued2009
 
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.
 
dc.description.naturepostprint
 
dc.identifier.citationBiochemical And Biophysical Research Communications, 2009, v. 390 n. 3, p. 404-409 [How to Cite?]
DOI: http://dx.doi.org/10.1016/j.bbrc.2009.09.029
 
dc.identifier.citeulike5796592
 
dc.identifier.doihttp://dx.doi.org/10.1016/j.bbrc.2009.09.029
 
dc.identifier.epage409
 
dc.identifier.hkuros170375
 
dc.identifier.isiWOS:000272516700011
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.

 
dc.identifier.issn0006-291X
2013 Impact Factor: 2.281
 
dc.identifier.issue3
 
dc.identifier.openurl
 
dc.identifier.pmcidPMC2787893
 
dc.identifier.pmid19748484
 
dc.identifier.scopuseid_2-s2.0-70449701456
 
dc.identifier.spage404
 
dc.identifier.urihttp://hdl.handle.net/10722/65599
 
dc.identifier.volume390
 
dc.languageeng
 
dc.publisherAcademic Press. The Journal's web site is located at http://www.elsevier.com/wps/find/journaldescription.cws_home/622790/description
 
dc.publisher.placeUnited States
 
dc.relation.ispartofBiochemical and Biophysical Research Communications
 
dc.relation.referencesReferences in Scopus
 
dc.rightsCreative Commons: Attribution 3.0 Hong Kong License
 
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.subjectAntibody
 
dc.subjectEscape
 
dc.subjectGermline
 
dc.subjectHIV
 
dc.subjectImmune responses
 
dc.subjectVaccine
 
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 immunogens
 
dc.typeArticle
 
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Author Affiliations
  1. National Cancer Institute at Frederick
  2. SAIC-Frederick
  3. National Institute of Allergy and Infectious Diseases