title: Towards covalent vaccination: improved polyclonal HIV neutralizing antibody response induced by an electrophilic gp120 V3 peptide analog.
abstract: Rare monoclonal antibodies (Abs) can form irreversible complexes with antigens by enzyme-like covalent nucleophile-electrophile pairing. To determine the feasibility of applying irreversible antigen inactivation by Abs as the basis of vaccination against microbes, we studied the polyclonal nucleophilic Ab response induced by the electrophilic analog of a synthetic peptide corresponding to the principal neutralizing determinant (PND) of human immunodeficiency virus type-1 (HIV) gp120 located in the V3 domain. Abs from mice immunized with the PND analog containing electrophilic phosphonates (E-PND) neutralized a homologous HIV strain (MN) approximately 50-fold more potently than control Abs from mice immunized with PND. The IgG fractions displayed binding to intact HIV particles. HIV complexes formed by anti-E-PND IgG dissociated noticeably more slowly than the complexes formed by anti-PND IgG. The slower dissociation kinetics are predicted to maintain long-lasting blockade of host cell receptor recognition by gp120. Pretreatment of the anti-PND IgG with a haptenic electrophilic phosphonate compound resulted in more rapid dissociation of the HIV-IgG complexes, consistent with the hypothesis that enhanced Ab nucleophilic reactivity induced by electrophilic immunization imparts irreversible character to the complexes. These results suggest that electrophilic immunization induces a sufficiently robust nucleophilic Ab response to enhance the anti-microbial efficacy of candidate polypeptide vaccines.
authors.affiliation: Chemical Immunology Research Center, Department of Pathology and Laboratory Medicine, University of Texas--Houston Medical School, Houston, Texas 77030, USA. Yasuhiro.Nishiyama@uth.tmc.edu
authors.forename: Yasuhiro
authors.initials: Y
authors.lastname: Nishiyama
authors.forename: Yukie
authors.initials: Y
authors.lastname: Mitsuda
authors.forename: Hiroaki
authors.initials: H
authors.lastname: Taguchi
authors.forename: Stephanie
authors.initials: S
authors.lastname: Planque
authors.forename: Maria
authors.initials: M
authors.lastname: Salas
authors.forename: Carl V
authors.initials: CV
authors.lastname: Hanson
authors.forename: Sudhir
authors.initials: S
authors.lastname: Paul
mesh_terms: D016915:AIDS Vaccines / Q000276:immunology*; D005240:Feasibility Studies; D015483:HIV Antibodies / Q000276:immunology* / Q000494:pharmacology*; D015699:HIV Envelope Protein gp120 / Q000276:immunology*; D015497:HIV-1 / Q000276:immunology*; D006801:Humans; D018448:Models, Immunological; D009500:Neutralization Tests
chemical_list: D016915:AIDS Vaccines; D015483:HIV Antibodies; D015699:HIV Envelope Protein gp120