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Functional, non-clonal IgMa-restricted B cell receptor interactions with the HIV-1 envelope gp41 membrane proximal external region.

Publication ,  Journal Article
Verkoczy, L; Moody, MA; Holl, TM; Bouton-Verville, H; Scearce, RM; Hutchinson, J; Alam, SM; Kelsoe, G; Haynes, BF
Published in: PLoS One
October 6, 2009

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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Published In

PLoS One

DOI

EISSN

1932-6203

Publication Date

October 6, 2009

Volume

4

Issue

10

Start / End Page

e7215

Location

United States

Related Subject Headings

  • Spleen
  • Signal Transduction
  • Protein Binding
  • Mice, Inbred C57BL
  • Mice, Inbred BALB C
  • Mice
  • Lymphocyte Activation
  • HIV-1
  • HIV Envelope Protein gp41
  • General Science & Technology
 

Citation

APA
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MLA
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Verkoczy, L., Moody, M. A., Holl, T. M., Bouton-Verville, H., Scearce, R. M., Hutchinson, J., … Haynes, B. F. (2009). Functional, non-clonal IgMa-restricted B cell receptor interactions with the HIV-1 envelope gp41 membrane proximal external region. PLoS One, 4(10), e7215. https://doi.org/10.1371/journal.pone.0007215
Verkoczy, Laurent, M Anthony Moody, T Matt Holl, Hilary Bouton-Verville, Richard M. Scearce, Jennifer Hutchinson, S Munir Alam, Garnett Kelsoe, and Barton F. Haynes. “Functional, non-clonal IgMa-restricted B cell receptor interactions with the HIV-1 envelope gp41 membrane proximal external region.PLoS One 4, no. 10 (October 6, 2009): e7215. https://doi.org/10.1371/journal.pone.0007215.
Verkoczy L, Moody MA, Holl TM, Bouton-Verville H, Scearce RM, Hutchinson J, et al. Functional, non-clonal IgMa-restricted B cell receptor interactions with the HIV-1 envelope gp41 membrane proximal external region. PLoS One. 2009 Oct 6;4(10):e7215.
Verkoczy, Laurent, et al. “Functional, non-clonal IgMa-restricted B cell receptor interactions with the HIV-1 envelope gp41 membrane proximal external region.PLoS One, vol. 4, no. 10, Oct. 2009, p. e7215. Pubmed, doi:10.1371/journal.pone.0007215.
Verkoczy L, Moody MA, Holl TM, Bouton-Verville H, Scearce RM, Hutchinson J, Alam SM, Kelsoe G, Haynes BF. Functional, non-clonal IgMa-restricted B cell receptor interactions with the HIV-1 envelope gp41 membrane proximal external region. PLoS One. 2009 Oct 6;4(10):e7215.

Published In

PLoS One

DOI

EISSN

1932-6203

Publication Date

October 6, 2009

Volume

4

Issue

10

Start / End Page

e7215

Location

United States

Related Subject Headings

  • Spleen
  • Signal Transduction
  • Protein Binding
  • Mice, Inbred C57BL
  • Mice, Inbred BALB C
  • Mice
  • Lymphocyte Activation
  • HIV-1
  • HIV Envelope Protein gp41
  • General Science & Technology