Deficient synthesis of class-switched, HIVneutralizing antibodies to the CD4 binding site and correction by electrophilic gp120 immunogen

Stephanie A. Planque, Yukie Mitsuda, Vida Chitsazzadeh, Santhi Gorantla, Larisa Poluektova, Yasuhiro Nishiyama, Christina Ochsenbauer, Mary Kate Morris, Gopal Sapparapu, Carl V. Hanson, Richard J. Massey, Sudhir Paul

Research output: Contribution to journalArticlepeer-review

3 Scopus citations

Abstract

Objective: HIV is vulnerable to antibodies that recognize a linear CD4 binding site epitope of gp120 (CLIN), but inducing CLIN-directed antibody synthesis by traditional vaccine principles is difficult. We wished to understand the basis for deficient CLIN- directed antibody synthesis and validate correction of the deficiency by an electrophilic gp120 analog (E-gp120) immunogen that binds B-cell receptors covalently. Methods: Serum antibody responses to a CLIN peptide and full-length gp120 epitopes induced by HIV infection in humans and immunization of mice with gp120 or E-gp120 were monitored. HIV neutralization by monoclonal and variable domain-swapped antibodies was determined from tissue culture and humanized mouse infection assays. Results: We describe deficient CLIN-directed IgG but not IgMantibodies in HIV-infected patients and mice immunized with gp120 accompanied by robust synthesis of IgGs to the immunodominant gp120 epitopes. Immunization with the E-gp120 corrected the deficient CLIN-directed IgG synthesis without overall increased immunogenicity of the CLIN or other gp120 epitopes. E-gp120-induced monoclonal IgGs neutralized diverse HIV strains heterologous to the immunogen. A CLIN-directed IgG neutralized HIV more potently compared to its larger IgM counterpart containing the same variable domains, suggesting obstructed access to HIV surface-expressed CLIN. An E-gp120-induced IgG suppressed HIV infection in humanized mice, validating the tissue culture neutralizing activity. Conclusion: A CLIN-selective physiological defect of IgM→IgG class-switch recombination (CSR) or restricted post-CSR B-cell development limits the functional utility of the humoral immune response to gp120. The E-gp120 immunogen is useful to bypass the restriction and induce broadly neutralizing CLIN-directed IgGs (see Supplemental Video.

Original languageEnglish (US)
Pages (from-to)2201-2211
Number of pages11
JournalAIDS
Volume28
Issue number15
DOIs
StatePublished - 2014

Keywords

  • Broadly neutralizing antibodies
  • CD4 binding site
  • Class-switch recombination
  • Covalent immunization
  • Superantigen epitope

ASJC Scopus subject areas

  • Immunology and Allergy
  • Immunology
  • Infectious Diseases

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