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Modulation of nonneutralizing HIV-1 gp41 responses by an MHC-restricted TH epitope overlapping those of membrane proximal external region broadly neutralizing antibodies.

Publication ,  Journal Article
Zhang, J; Alam, SM; Bouton-Verville, H; Chen, Y; Newman, A; Stewart, S; Jaeger, FH; Montefiori, DC; Dennison, SM; Haynes, BF; Verkoczy, L
Published in: J Immunol
February 15, 2014

A goal of HIV-1 vaccine development is to elicit broadly neutralizing Abs (BnAbs), but current immunization strategies fail to induce BnAbs, and for unknown reasons, often induce nonneutralizing Abs instead. To explore potential host genetic contributions controlling Ab responses to the HIV-1 Envelope, we have used congenic strains to identify a critical role for MHC class II restriction in modulating Ab responses to the membrane proximal external region (MPER) of gp41, a key vaccine target. Immunized H-2(d)-congenic strains had more rapid, sustained, and elevated MPER(+) Ab titers than those bearing other haplotypes, regardless of immunogen, adjuvant, or prime or boost regimen used, including formulations designed to provide T cell help. H-2(d)-restricted MPER(+) serum Ab responses depended on CD4 TH interactions with class II (as revealed in immunized intra-H-2(d/b) congenic or CD154(-/-) H-2(d) strains, and by selective abrogation of MPER restimulated, H-2(d)-restricted primed splenocytes by class II-blocking Abs), and failed to neutralize HIV-1 in the TZM-b/l neutralization assay, coinciding with lack of specificity for an aspartate residue in the neutralization core of BnAb 2F5. Unexpectedly, H-2(d)-restricted MPER(+) responses functionally mapped to a core TH epitope partially overlapping the 2F5/z13/4E10 BnAb epitopes as well as nonneutralizing B cell-Ab binding residues. We propose that class II restriction contributes to the general heterogeneity of nonneutralizing gp41 responses induced by Envelope. Moreover, the proximity of TH and B cell epitopes in this restriction may have to be considered in redesigning minimal MPER immunogens aimed at exclusively binding BnAb epitopes and triggering MPER(+) BnAbs.

Duke Scholars

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Published In

J Immunol

DOI

EISSN

1550-6606

Publication Date

February 15, 2014

Volume

192

Issue

4

Start / End Page

1693 / 1706

Location

United States

Related Subject Headings

  • T-Lymphocytes, Helper-Inducer
  • Mice, Inbred C57BL
  • Mice, Inbred BALB C
  • Mice
  • Immunology
  • Histocompatibility Antigens Class II
  • HIV Envelope Protein gp41
  • HIV Antibodies
  • Epitopes, T-Lymphocyte
  • Cell Proliferation
 

Citation

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ICMJE
MLA
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Zhang, J., Alam, S. M., Bouton-Verville, H., Chen, Y., Newman, A., Stewart, S., … Verkoczy, L. (2014). Modulation of nonneutralizing HIV-1 gp41 responses by an MHC-restricted TH epitope overlapping those of membrane proximal external region broadly neutralizing antibodies. J Immunol, 192(4), 1693–1706. https://doi.org/10.4049/jimmunol.1302511
Zhang, Jinsong, S Munir Alam, Hilary Bouton-Verville, Yao Chen, Amanda Newman, Shelley Stewart, Frederick H. Jaeger, et al. “Modulation of nonneutralizing HIV-1 gp41 responses by an MHC-restricted TH epitope overlapping those of membrane proximal external region broadly neutralizing antibodies.J Immunol 192, no. 4 (February 15, 2014): 1693–1706. https://doi.org/10.4049/jimmunol.1302511.
Zhang J, Alam SM, Bouton-Verville H, Chen Y, Newman A, Stewart S, et al. Modulation of nonneutralizing HIV-1 gp41 responses by an MHC-restricted TH epitope overlapping those of membrane proximal external region broadly neutralizing antibodies. J Immunol. 2014 Feb 15;192(4):1693–706.
Zhang, Jinsong, et al. “Modulation of nonneutralizing HIV-1 gp41 responses by an MHC-restricted TH epitope overlapping those of membrane proximal external region broadly neutralizing antibodies.J Immunol, vol. 192, no. 4, Feb. 2014, pp. 1693–706. Pubmed, doi:10.4049/jimmunol.1302511.
Zhang J, Alam SM, Bouton-Verville H, Chen Y, Newman A, Stewart S, Jaeger FH, Montefiori DC, Dennison SM, Haynes BF, Verkoczy L. Modulation of nonneutralizing HIV-1 gp41 responses by an MHC-restricted TH epitope overlapping those of membrane proximal external region broadly neutralizing antibodies. J Immunol. 2014 Feb 15;192(4):1693–1706.

Published In

J Immunol

DOI

EISSN

1550-6606

Publication Date

February 15, 2014

Volume

192

Issue

4

Start / End Page

1693 / 1706

Location

United States

Related Subject Headings

  • T-Lymphocytes, Helper-Inducer
  • Mice, Inbred C57BL
  • Mice, Inbred BALB C
  • Mice
  • Immunology
  • Histocompatibility Antigens Class II
  • HIV Envelope Protein gp41
  • HIV Antibodies
  • Epitopes, T-Lymphocyte
  • Cell Proliferation