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Induction of HIV-1 broad neutralizing antibodies in 2F5 knock-in mice: selection against membrane proximal external region-associated autoreactivity limits T-dependent responses.

Publication ,  Journal Article
Verkoczy, L; Chen, Y; Zhang, J; Bouton-Verville, H; Newman, A; Lockwood, B; Scearce, RM; Montefiori, DC; Dennison, SM; Xia, S-M; Hwang, K-K ...
Published in: J Immunol
September 1, 2013

A goal of HIV-1 vaccine development is to elicit broadly neutralizing Abs (BnAbs). Using a knock-in (KI) model of 2F5, a human HIV-1 gp41 membrane proximal external region (MPER)-specific BnAb, we previously demonstrated that a key obstacle to BnAb induction is clonal deletion of BnAb-expressing B cells. In this study of this model, we provide a proof-of-principle that robust serum neutralizing IgG responses can be induced from pre-existing, residual, self-reactive BnAb-expressing B cells in vivo using a structurally compatible gp41 MPER immunogen. Furthermore, in CD40L-deficient 2F5 KI mice, we demonstrate that these BnAb responses are elicited via a type II T-independent pathway, coinciding with expansion and activation of transitional splenic B cells specific for 2F5's nominal gp41 MPER-binding epitope (containing the 2F5 neutralization domain ELDKWA). In contrast, constitutive production of nonneutralizing serum IgGs in 2F5 KI mice is T dependent and originates from a subset of splenic mature B2 cells that have lost their ability to bind 2F5's gp41 MPER epitope. These results suggest that residual, mature B cells expressing autoreactive BnAbs, like 2F5 as BCR, may be limited in their ability to participate in T-dependent responses by purifying selection that selectively eliminates reactivity for neutralization epitope-containing/mimicked host Ags.

Duke Scholars

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Published In

J Immunol

DOI

EISSN

1550-6606

Publication Date

September 1, 2013

Volume

191

Issue

5

Start / End Page

2538 / 2550

Location

United States

Related Subject Headings

  • T-Lymphocytes
  • Neutralization Tests
  • Mice, Knockout
  • Mice
  • Lymphocyte Activation
  • Immunology
  • Humans
  • HIV-1
  • HIV Envelope Protein gp41
  • HIV Antibodies
 

Citation

APA
Chicago
ICMJE
MLA
NLM
Verkoczy, L., Chen, Y., Zhang, J., Bouton-Verville, H., Newman, A., Lockwood, B., … Haynes, B. F. (2013). Induction of HIV-1 broad neutralizing antibodies in 2F5 knock-in mice: selection against membrane proximal external region-associated autoreactivity limits T-dependent responses. J Immunol, 191(5), 2538–2550. https://doi.org/10.4049/jimmunol.1300971
Verkoczy, Laurent, Yao Chen, Jinsong Zhang, Hilary Bouton-Verville, Amanda Newman, Bradley Lockwood, Richard M. Scearce, et al. “Induction of HIV-1 broad neutralizing antibodies in 2F5 knock-in mice: selection against membrane proximal external region-associated autoreactivity limits T-dependent responses.J Immunol 191, no. 5 (September 1, 2013): 2538–50. https://doi.org/10.4049/jimmunol.1300971.
Verkoczy, Laurent, et al. “Induction of HIV-1 broad neutralizing antibodies in 2F5 knock-in mice: selection against membrane proximal external region-associated autoreactivity limits T-dependent responses.J Immunol, vol. 191, no. 5, Sept. 2013, pp. 2538–50. Pubmed, doi:10.4049/jimmunol.1300971.
Verkoczy L, Chen Y, Zhang J, Bouton-Verville H, Newman A, Lockwood B, Scearce RM, Montefiori DC, Dennison SM, Xia S-M, Hwang K-K, Liao H-X, Alam SM, Haynes BF. Induction of HIV-1 broad neutralizing antibodies in 2F5 knock-in mice: selection against membrane proximal external region-associated autoreactivity limits T-dependent responses. J Immunol. 2013 Sep 1;191(5):2538–2550.

Published In

J Immunol

DOI

EISSN

1550-6606

Publication Date

September 1, 2013

Volume

191

Issue

5

Start / End Page

2538 / 2550

Location

United States

Related Subject Headings

  • T-Lymphocytes
  • Neutralization Tests
  • Mice, Knockout
  • Mice
  • Lymphocyte Activation
  • Immunology
  • Humans
  • HIV-1
  • HIV Envelope Protein gp41
  • HIV Antibodies