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J. Biol. Chem., Vol. 282, Issue 43, 31250-31256, October 26, 2007

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Towards Covalent Vaccination

IMPROVED POLYCLONAL HIV NEUTRALIZING ANTIBODY RESPONSE INDUCED BY AN ELECTROPHILIC gp120 V3 PEPTIDE ANALOG^*

Yasuhiro Nishiyama¹, Yukie Mitsuda, Hiroaki Taguchi, Stephanie Planque, Maria Salas, Carl V. Hanson, and Sudhir Paul²

From the Chemical Immunology Research Center, Department of Pathology and Laboratory Medicine, University of Texas-Houston Medical School, Houston, Texas 77030 and the Viral and Rickettsial Disease Laboratory, California Department of Public Health, Richmond, California 94804

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) 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.

Received for publication, August 6, 2007 , and in revised form, August 15, 2007.

^* This work was supported by National Institutes of Health Grants, R01AI058865, R01AI067020, R21AI062455, and R21AI071951. The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked "advertisement"in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

¹ To whom correspondence may be addressed: Chemical Immunology Research Center, Dept. of Pathology and Laboratory Medicine, University of Texas-Houston Medical School, 6431 Fannin, Houston, TX 77030. E-mail: Yasuhiro.Nishiyama{at}uth.tmc.edu. ² To whom correspondence may be addressed: Chemical Immunology Research Center, Dept. of Pathology and Laboratory Medicine, University of Texas-Houston Medical School, 6431 Fannin, Houston, TX 77030. E-mail: Sudhir.Paul{at}uth.tmc.edu.

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