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Journal of Virology, August 2005, p. 9872-9884, Vol. 79, No. 15
0022-538X/05/$08.00+0     doi:10.1128/JVI.79.15.9872-9884.2005
Copyright © 2005, American Society for Microbiology. All Rights Reserved.

Induction of Neutralizing Antibodies and Th1-Polarized and CD4-Independent CD8+ T-Cell Responses following Delivery of Human Immunodeficiency Virus Type 1 Tat Protein by Recombinant Adenylate Cyclase of Bordetella pertussis

Laurent Mascarell,1 Catherine Fayolle,1 Cécile Bauche,2 Daniel Ladant,2 and Claude Leclerc1*

Unité de Biologie des Régulations Immunitaires, INSERM E 352,1 Unité de Biochimie des Interactions Macromoléculaires, CNRS URA 2185, Institut Pasteur, 75724 Paris, France2

Received 22 February 2005/ Accepted 19 April 2005

HIV-Tat, a conserved protein playing a key role in the early life cycle of the human immunodeficiency virus (HIV) has been proposed as a potential AIDS vaccine. An HIV-Tat-based vaccine should elicit a broad, long-lasting, and neutralizing immune response. We have previously demonstrated that the adenylate cyclase (CyaA) from Bordetella pertussis targets dendritic cells and delivers CD8+ and CD4+ T-cell epitopes into the major histocompatibility complex class I and class II presentation pathways. We have also showed that CyaA induced specific and protective cytotoxic T cell responses in vivo. Here, we designed a prototype vaccine based on the HIV type 1 Tat delivered by CyaA (CyaA-E5-Tat) and tested its capacity to induce HIV-Tat-specific cellular as well as antibody responses. We showed that immunization of mice by CyaA-E5-Tat in the absence of adjuvant elicited strong and long-lasting neutralizing anti-Tat antibody responses more efficient than those obtained after immunization with Tat toxoid in aluminum hydroxide adjuvant. Analyses of the anti-Tat immunoglobulin G isotypes and the cytokine pattern showed that CyaA-E5-Tat induced a Th1-polarized immune response in contrast to the Th2-polarized immune responses obtained with the Tat toxoid. In addition, our data demonstrated that HIV-Tat-specific gamma interferon-producing CD8+ T cells were generated after vaccination with CyaA-E5-Tat in a CD4+ T-cell-independent manner. Based on these findings, CyaA-E5-Tat represents an attractive vaccine candidate for both preventive and therapeutic vaccination involving CyaA as an efficient nonreplicative vector for protein delivery.

* Corresponding author. Mailing address: Biologie des Régulations Immunitaires, INSERM E 352, Institut Pasteur, 25 rue du Docteur Roux, 75724 Paris cedex 15, France. Phone: 33 1 45 68 86 18. Fax: 33 1 45 68 85 40. E-mail: cleclerc{at}pasteur.fr.

Journal of Virology, August 2005, p. 9872-9884, Vol. 79, No. 15
0022-538X/05/$08.00+0     doi:10.1128/JVI.79.15.9872-9884.2005
Copyright © 2005, American Society for Microbiology. All Rights Reserved.



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