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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Bibliographic Details
Published in:PloS one Vol. 4; no. 10; p. e7215
Main Authors: Verkoczy, Laurent, Moody, M. Anthony, Holl, T. Matt, Bouton-Verville, Hilary, Scearce, Richard M., Hutchinson, Jennifer, Alam, S. Munir, Kelsoe, Garnett, Haynes, Barton F.
Format: Journal Article
Language:English
Published: United States Public Library of Science 06.10.2009
Public Library of Science (PLoS)
Subjects:
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
North Carolina
United States > US
ISSN:1932-6203, 1932-6203
Online Access:Get full text
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Summary: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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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.
ISSN:1932-6203
1932-6203
DOI:10.1371/journal.pone.0007215