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Journal of Virology, April 2005, p. 4033-4042, Vol. 79, No. 7
0022-538X/05/$08.00+0     doi:10.1128/JVI.79.7.4033-4042.2005
Copyright © 2005, American Society for Microbiology. All Rights Reserved.

Circumventing Tolerance to the Prion Protein (PrP): Vaccination with PrP-Displaying Retrovirus Particles Induces Humoral Immune Responses against the Native Form of Cellular PrP

Daphne Nikles,^1, Patricia Bach,^2, Klaus Boller,² Christoph A. Merten,¹ Fabio Montrasio,³ Frank L. Heppner,⁴ Adriano Aguzzi,⁴ Klaus Cichutek,¹ Ulrich Kalinke,^2* and Christian J. Buchholz^1*

Divisions of Medical Biotechnology,¹ Immunology,² Prion Research, Paul-Ehrlich-Institut, Langen, Germany,³ Institute of Neuropathology, University Hospital Zürich, Zurich, Switzerland⁴

Received 9 June 2004/ Accepted 5 November 2004

Passive immunization with antibodies directed against the cellular form of the prion protein (PrP^C) can protect against prion disease. However, active immunization with recombinant prion protein has so far failed to induce antibodies directed against native PrP^C expressed on the cell surface. To develop an antiprion vaccine, a retroviral display system presenting either the full-length mouse PrP (PrP209) or the C-terminal 111 amino acids (PrP111) fused to the transmembrane domain of the platelet-derived growth factor receptor was established. Western blot analysis and immunogold electron microscopy of the retroviral display particles revealed successful incorporation of the fusion proteins into the particle membrane. Interestingly, retroviral particles displaying PrP111 (PrP^D111 retroparticles) showed higher incorporation efficiencies than those displaying PrP209. Already 7 days after intravenous injection of PrP^D111 retroparticles, PrP^C-deficient mice (Prnp^o/o) showed high immunoglobulin M (IgM) and IgG titers specifically binding the native PrP^C molecule as expressed on the surface of T cells isolated from PrP^C-overexpressing transgenic mice. More importantly, heterozygous Prnp^+/o mice and also wild-type mice showed PrP^C-specific IgM and IgG antibodies upon vaccination with PrP^D111 retroparticles, albeit at considerably lower levels. Bacterially expressed recombinant PrP, in contrast, was unable to evoke IgG antibodies recognizing native PrP^C in wild-type mice. Thus, our data show that PrP or parts thereof can be functionally displayed on retroviral particles and that immunization with PrP retroparticles may serve as a novel promising strategy for vaccination against transmissible spongiform encephalitis.

D.N. and P.B. contributed equally to this work.

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