Functional, Non-Clonal IgMa-Restricted B Cell Receptor Interactions with the HIV-1 Envelope gp41 Membrane Proximal External Region
The membrane proximal external region (MPER) of HIV-1 gp41 has several features that make it an attractive antibody-based vaccine target, but eliciting an effective gp41 MPER-specific protective antibody response remains elusive. One fundamental issue is whether the failure to make gp41 MPER-specifi...
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| Vydané v: | PloS one Ročník 4; číslo 10; s. e7215 |
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| Hlavní autori: | , , , , , , , , |
| Médium: | Journal Article |
| Jazyk: | English |
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United States
Public Library of Science
06.10.2009
Public Library of Science (PLoS) |
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| ISSN: | 1932-6203, 1932-6203 |
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| Abstract | The membrane proximal external region (MPER) of HIV-1 gp41 has several features that make it an attractive antibody-based vaccine target, but eliciting an effective gp41 MPER-specific protective antibody response remains elusive. One fundamental issue is whether the failure to make gp41 MPER-specific broadly neutralizing antibodies like 2F5 and 4E10 is due to structural constraints with the gp41 MPER, or alternatively, if gp41 MPER epitope-specific B cells are lost to immunological tolerance. An equally important question is how B cells interact with, and respond to, the gp41 MPER epitope, including whether they engage this epitope in a non-canonical manner i.e., by non-paratopic recognition via B cell receptors (BCR). To begin understanding how B cells engage the gp41 MPER, we characterized B cell-gp41 MPER interactions in BALB/c and C57BL/6 mice. Surprisingly, we found that a significant (approximately 7%) fraction of splenic B cells from BALB/c, but not C57BL/6 mice, bound the gp41 MPER via their BCRs. This strain-specific binding was concentrated in IgM(hi) subsets, including marginal zone and peritoneal B1 B cells, and correlated with enriched fractions (approximately 15%) of gp41 MPER-specific IgM secreted by in vitro-activated splenic B cells. Analysis of Igh(a) (BALB/c) and Igh(b) (C57BL/6) congenic mice demonstrated that gp41 MPER binding was controlled by determinants of the Igh(a) locus. Mapping of MPER gp41 interactions with IgM(a) identified MPER residues distinct from those to which mAb 2F5 binds and demonstrated the requirement of Fc C(H) regions. Importantly, gp41 MPER ligation produced detectable BCR-proximal signaling events, suggesting that interactions between gp41 MPER and IgM(a) determinants may elicit partial B cell activation. These data suggest that low avidity, non-paratopic interactions between the gp41 MPER and membrane Ig on naïve B cells may interfere with or divert bnAb responses. |
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| AbstractList | The membrane proximal external region (MPER) of HIV-1 gp41 has several features that make it an attractive antibody-based vaccine target, but eliciting an effective gp41 MPER-specific protective antibody response remains elusive. One fundamental issue is whether the failure to make gp41 MPER-specific broadly neutralizing antibodies like 2F5 and 4E10 is due to structural constraints with the gp41 MPER, or alternatively, if gp41 MPER epitope-specific B cells are lost to immunological tolerance. An equally important question is how B cells interact with, and respond to, the gp41 MPER epitope, including whether they engage this epitope in a non-canonical manner i.e., by non-paratopic recognition via B cell receptors (BCR). To begin understanding how B cells engage the gp41 MPER, we characterized B cell-gp41 MPER interactions in BALB/c and C57BL/6 mice. Surprisingly, we found that a significant (approximately 7%) fraction of splenic B cells from BALB/c, but not C57BL/6 mice, bound the gp41 MPER via their BCRs. This strain-specific binding was concentrated in IgM(hi) subsets, including marginal zone and peritoneal B1 B cells, and correlated with enriched fractions (approximately 15%) of gp41 MPER-specific IgM secreted by in vitro-activated splenic B cells. Analysis of Igh(a) (BALB/c) and Igh(b) (C57BL/6) congenic mice demonstrated that gp41 MPER binding was controlled by determinants of the Igh(a) locus. Mapping of MPER gp41 interactions with IgM(a) identified MPER residues distinct from those to which mAb 2F5 binds and demonstrated the requirement of Fc C(H) regions. Importantly, gp41 MPER ligation produced detectable BCR-proximal signaling events, suggesting that interactions between gp41 MPER and IgM(a) determinants may elicit partial B cell activation. These data suggest that low avidity, non-paratopic interactions between the gp41 MPER and membrane Ig on naïve B cells may interfere with or divert bnAb responses. The membrane proximal external region (MPER) of HIV-1 gp41 has several features that make it an attractive antibody-based vaccine target, but eliciting an effective gp41 MPER-specific protective antibody response remains elusive. One fundamental issue is whether the failure to make gp41 MPER-specific broadly neutralizing antibodies like 2F5 and 4E10 is due to structural constraints with the gp41 MPER, or alternatively, if gp41 MPER epitope-specific B cells are lost to immunological tolerance. An equally important question is how B cells interact with, and respond to, the gp41 MPER epitope, including whether they engage this epitope in a non-canonical manner i.e., by non-paratopic recognition via B cell receptors (BCR). To begin understanding how B cells engage the gp41 MPER, we characterized B cell-gp41 MPER interactions in BALB/c and C57BL/6 mice. Surprisingly, we found that a significant (approximately 7%) fraction of splenic B cells from BALB/c, but not C57BL/6 mice, bound the gp41 MPER via their BCRs. This strain-specific binding was concentrated in IgM(hi) subsets, including marginal zone and peritoneal B1 B cells, and correlated with enriched fractions (approximately 15%) of gp41 MPER-specific IgM secreted by in vitro-activated splenic B cells. Analysis of Igh(a) (BALB/c) and Igh(b) (C57BL/6) congenic mice demonstrated that gp41 MPER binding was controlled by determinants of the Igh(a) locus. Mapping of MPER gp41 interactions with IgM(a) identified MPER residues distinct from those to which mAb 2F5 binds and demonstrated the requirement of Fc C(H) regions. Importantly, gp41 MPER ligation produced detectable BCR-proximal signaling events, suggesting that interactions between gp41 MPER and IgM(a) determinants may elicit partial B cell activation. These data suggest that low avidity, non-paratopic interactions between the gp41 MPER and membrane Ig on naïve B cells may interfere with or divert bnAb responses.The membrane proximal external region (MPER) of HIV-1 gp41 has several features that make it an attractive antibody-based vaccine target, but eliciting an effective gp41 MPER-specific protective antibody response remains elusive. One fundamental issue is whether the failure to make gp41 MPER-specific broadly neutralizing antibodies like 2F5 and 4E10 is due to structural constraints with the gp41 MPER, or alternatively, if gp41 MPER epitope-specific B cells are lost to immunological tolerance. An equally important question is how B cells interact with, and respond to, the gp41 MPER epitope, including whether they engage this epitope in a non-canonical manner i.e., by non-paratopic recognition via B cell receptors (BCR). To begin understanding how B cells engage the gp41 MPER, we characterized B cell-gp41 MPER interactions in BALB/c and C57BL/6 mice. Surprisingly, we found that a significant (approximately 7%) fraction of splenic B cells from BALB/c, but not C57BL/6 mice, bound the gp41 MPER via their BCRs. This strain-specific binding was concentrated in IgM(hi) subsets, including marginal zone and peritoneal B1 B cells, and correlated with enriched fractions (approximately 15%) of gp41 MPER-specific IgM secreted by in vitro-activated splenic B cells. Analysis of Igh(a) (BALB/c) and Igh(b) (C57BL/6) congenic mice demonstrated that gp41 MPER binding was controlled by determinants of the Igh(a) locus. Mapping of MPER gp41 interactions with IgM(a) identified MPER residues distinct from those to which mAb 2F5 binds and demonstrated the requirement of Fc C(H) regions. Importantly, gp41 MPER ligation produced detectable BCR-proximal signaling events, suggesting that interactions between gp41 MPER and IgM(a) determinants may elicit partial B cell activation. These data suggest that low avidity, non-paratopic interactions between the gp41 MPER and membrane Ig on naïve B cells may interfere with or divert bnAb responses. The membrane proximal external region (MPER) of HIV-1 gp41 has several features that make it an attractive antibody-based vaccine target, but eliciting an effective gp41 MPER-specific protective antibody response remains elusive. One fundamental issue is whether the failure to make gp41 MPER-specific broadly neutralizing antibodies like 2F5 and 4E10 is due to structural constraints with the gp41 MPER, or alternatively, if gp41 MPER epitope-specific B cells are lost to immunological tolerance. An equally important question is how B cells interact with, and respond to, the gp41 MPER epitope, including whether they engage this epitope in a non-canonical manner i.e., by non-paratopic recognition via B cell receptors (BCR). To begin understanding how B cells engage the gp41 MPER, we characterized B cell-gp41 MPER interactions in BALB/c and C57BL/6 mice. Surprisingly, we found that a significant (∼7%) fraction of splenic B cells from BALB/c, but not C57BL/6 mice, bound the gp41 MPER via their BCRs. This strain-specific binding was concentrated in IgMhi subsets, including marginal zone and peritoneal B1 B cells, and correlated with enriched fractions (∼15%) of gp41 MPER-specific IgM secreted by in vitro-activated splenic B cells. Analysis of Igha (BALB/c) and Ighb (C57BL/6) congenic mice demonstrated that gp41 MPER binding was controlled by determinants of the Igha locus. Mapping of MPER gp41 interactions with IgMa identified MPER residues distinct from those to which mAb 2F5 binds and demonstrated the requirement of Fc CH regions. Importantly, gp41 MPER ligation produced detectable BCR-proximal signaling events, suggesting that interactions between gp41 MPER and IgMa determinants may elicit partial B cell activation. These data suggest that low avidity, non-paratopic interactions between the gp41 MPER and membrane Ig on naïve B cells may interfere with or divert bnAb responses. |
| Author | Verkoczy, Laurent Alam, S. Munir Kelsoe, Garnett Hutchinson, Jennifer Bouton-Verville, Hilary Holl, T. Matt Scearce, Richard M. Haynes, Barton F. Moody, M. Anthony |
| AuthorAffiliation | New York University School of Medicine, United States of America 1 Human Vaccine Institute, Duke University Medical Center, Durham, North Carolina, United States of America 2 Department of Immunology, Duke University Medical Center, Durham, North Carolina, United States of America |
| AuthorAffiliation_xml | – name: New York University School of Medicine, United States of America – name: 1 Human Vaccine Institute, Duke University Medical Center, Durham, North Carolina, United States of America – name: 2 Department of Immunology, Duke University Medical Center, Durham, North Carolina, United States of America |
| Author_xml | – sequence: 1 givenname: Laurent surname: Verkoczy fullname: Verkoczy, Laurent – sequence: 2 givenname: M. Anthony surname: Moody fullname: Moody, M. Anthony – sequence: 3 givenname: T. Matt surname: Holl fullname: Holl, T. Matt – sequence: 4 givenname: Hilary surname: Bouton-Verville fullname: Bouton-Verville, Hilary – sequence: 5 givenname: Richard M. surname: Scearce fullname: Scearce, Richard M. – sequence: 6 givenname: Jennifer surname: Hutchinson fullname: Hutchinson, Jennifer – sequence: 7 givenname: S. Munir surname: Alam fullname: Alam, S. Munir – sequence: 8 givenname: Garnett surname: Kelsoe fullname: Kelsoe, Garnett – sequence: 9 givenname: Barton F. surname: Haynes fullname: Haynes, Barton F. |
| BackLink | https://www.ncbi.nlm.nih.gov/pubmed/19806186$$D View this record in MEDLINE/PubMed |
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| CitedBy_id | crossref_primary_10_1016_j_jviromet_2010_10_022 crossref_primary_10_1111_j_1747_0285_2012_01423_x crossref_primary_10_1084_jem_20110363 crossref_primary_10_4049_jimmunol_2100172 crossref_primary_10_1371_journal_pone_0023532 crossref_primary_10_4049_jimmunol_1302829 crossref_primary_10_1126_scitranslmed_aaf0618 crossref_primary_10_1016_j_coi_2011_04_003 crossref_primary_10_1371_journal_pone_0085098 crossref_primary_10_1111_imr_12504 crossref_primary_10_1007_s00018_021_04009_z crossref_primary_10_4049_jimmunol_1101633 crossref_primary_10_4049_jimmunol_1300770 crossref_primary_10_1126_sciimmunol_aag0851 crossref_primary_10_4049_jimmunol_1302511 crossref_primary_10_1371_journal_ppat_1005042 crossref_primary_10_4049_jimmunol_1300971 |
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| ContentType | Journal Article |
| Copyright | 2009 Verkoczy et al. This is an open-access article distributed under the terms of the Creative Commons Attribution License (the “License”), which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited. Notwithstanding the ProQuest Terms and Conditions, you may use this content in accordance with the terms of the License. Verkoczy et al. 2009 |
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| Notes | ObjectType-Article-1 SourceType-Scholarly Journals-1 ObjectType-Feature-2 content type line 14 content type line 23 Conceived and designed the experiments: LKV GHK BFH. Performed the experiments: TMH HBV RMS JH SMA. Analyzed the data: LKV TMH HBV SMA GHK BFH. Contributed reagents/materials/analysis tools: MAM BFH. Wrote the paper: LKV BFH. Played a key role in revising the paper: GHK. |
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| SubjectTerms | Animals Antibodies Antibody response Antigens Avidity B-Cell Activation Factor Receptor - metabolism B-cell receptor B-Lymphocytes - virology Binding CD79 Antigens - metabolism Cell activation Cell Membrane - metabolism Epitopes - chemistry Female Glycoprotein gp41 HIV HIV Envelope Protein gp41 - metabolism HIV-1 - metabolism Human immunodeficiency virus Immunoglobulin M Immunoglobulins Immunological tolerance Immunology Immunology/Genetics of the Immune System Immunology/Immune Response Immunology/Immunity to Infections Immunology/Immunomodulation Immunology/Leukocyte Signaling and Gene Expression Lymphocyte Activation Lymphocyte receptors Lymphocytes B Mice Mice, Inbred BALB C Mice, Inbred C57BL Monoclonal antibodies Peptides Peritoneum Protein Binding Receptors Signal Transduction Signaling Spleen Spleen - metabolism Vaccines Virology |
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| Title | Functional, Non-Clonal IgMa-Restricted B Cell Receptor Interactions with the HIV-1 Envelope gp41 Membrane Proximal External Region |
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