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Immune Focusing and Enhanced Neutralization Induced by HIV-1 gp140 Chemical Cross-Linking

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Overview

authors

  • Schiffner, T.
  • Kong, L.
  • Duncan, C. J. A.
  • Back, J. W.
  • Benschop, J. J.
  • Shen, X.
  • Huang, P. S.
  • Stewart-Jones, G. B.
  • DeStefano, J.
  • Seaman, M. S.
  • Tomaras, G. D.
  • Montefiori, D. C.
  • Schief, William
  • Sattentau, Q. J.

publication date

  • September 2013

journal

  • Journal of Virology  Journal

abstract

  • Experimental vaccine antigens based upon the HIV-1 envelope glycoproteins (Env) have failed to induce neutralizing antibodies (NAbs) against the majority of circulating viral strains as a result of antibody evasion mechanisms, including amino acid variability and conformational instability. A potential vaccine design strategy is to stabilize Env, thereby focusing antibody responses on constitutively exposed, conserved surfaces, such as the CD4 binding site (CD4bs). Here, we show that a largely trimeric form of soluble Env can be stably cross-linked with glutaraldehyde (GLA) without global modification of antigenicity. Cross-linking largely conserved binding of all potent broadly neutralizing antibodies (bNAbs) tested, including CD4bs-specific VRC01 and HJ16, but reduced binding of several non- or weakly neutralizing antibodies and soluble CD4 (sCD4). Adjuvanted administration of cross-linked or unmodified gp140 to rabbits generated indistinguishable total gp140-specific serum IgG binding titers. However, sera from animals receiving cross-linked gp140 showed significantly increased CD4bs-specific antibody binding compared to animals receiving unmodified gp140. Moreover, peptide mapping of sera from animals receiving cross-linked gp140 revealed increased binding to gp120 C1 and V1V2 regions. Finally, neutralization titers were significantly elevated in sera from animals receiving cross-linked gp140 rather than unmodified gp140. We conclude that cross-linking favors antigen stability, imparts antigenic modifications that selectively refocus antibody specificity and improves induction of NAbs, and might be a useful strategy for future vaccine design.

subject areas

  • AIDS Vaccines
  • Adjuvants, Immunologic
  • Animals
  • Antibodies, Neutralizing
  • Cross-Linking Reagents
  • HIV Antibodies
  • HIV Antigens
  • Rabbits
  • env Gene Products, Human Immunodeficiency Virus
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Identity

PubMed Central ID

  • PMC3754013

International Standard Serial Number (ISSN)

  • 0022-538X

Digital Object Identifier (DOI)

  • 10.1128/jvi.01161-13

PubMed ID

  • 23843636
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Additional Document Info

start page

  • 10163

end page

  • 10172

volume

  • 87

issue

  • 18

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