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Journal of Virology, August 2001, p. 7330-7338, Vol. 75, No. 16
0022-538X/01/$04.00+0 DOI: 10.1128/JVI.75.16.7330-7338.2001
Copyright © 2001, American Society for Microbiology. All rights reserved.
Delivery of Multiple Epitopes by Recombinant
Detoxified Adenylate Cyclase of Bordetella pertussis
Induces Protective Antiviral Immunity
Catherine
Fayolle,1
Adriana
Osickova,2
Radim
Osicka,2
Thomas
Henry,1
Marie-Jésus
Rojas,1
Marie-Françoise
Saron,3
Peter
Sebo,2 and
Claude
Leclerc1,*
Unité de Biologie des Régulations
Immunitaires1 and Unité
d'Histopathologie,3 Institut Pasteur, Paris,
France, and Cell and Molecular Microbiology Division,
Institute of Microbiology, Academy of Sciences, 142 20 Prague,
Czech Republic2
Received 20 December 2000/Accepted 15 May 2001
CyaA, the adenylate cyclase toxin from Bordetella
pertussis, can deliver its N-terminal catalytic domain into the
cytosol of a large number of eukaryotic cells and particularly into
professional antigen-presenting cells. We have previously identified
within the primary structure of CyaA several permissive sites at which insertion of peptides does not alter the ability of the toxin to enter
cells. This property has been exploited to design recombinant CyaA
toxoids capable of delivering major histocompatibility complex (MHC)
class I-restricted CD8+ T-cell epitopes into
antigen-presenting cells and to induce specific CD8+
cytotoxic T-lymphocyte (CTL) responses in vivo. Here we have explored
the capacity of the CyaA vector carrying several different CD8+ T-cell epitopes to prime multiple CTL responses. The
model vaccine consisted of a polyepitope made of three CTL epitopes
from lymphocytic choriomeningitis virus (LCMV), the V3 region of human
immunodeficiency virus gp120, and chicken ovalbumin, inserted at three
different sites of the catalytic domain of genetically detoxified CyaA. Each of these epitopes was processed on delivery by CyaA and presented in vitro to specific T-cell hybridomas. Immunization of mice by CyaA
toxoids carrying the polyepitope lead to the induction of specific CTL
responses for each of the three epitopes, as well as to protection
against a lethal viral challenge. Moreover, mice primed against the
vector by mock CyaA or a recombinant toxoid were still able to develop
strong CTL responses after subsequent immunization with a recombinant
CyaA carrying a foreign CD8+ CTL epitope. These results
highlight the potency of the adenylate cyclase vector for induction of
protective CTL responses with multiple specificity and/or broad MHC restriction.
*
Corresponding author. Mailing address: Unité de
Biologie des Régulations Immunitaires, 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 2001, p. 7330-7338, Vol. 75, No. 16
0022-538X/01/$04.00+0 DOI: 10.1128/JVI.75.16.7330-7338.2001
Copyright © 2001, American Society for Microbiology. All rights reserved.
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