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This Article Full Text Full Text (PDF) All Versions of this Article: jimmunol.0901596v1 183/10/6145    most recent Alert me when this article is cited Alert me if a correction is posted Citation Map Services Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Request Permissions Google Scholar Articles by Basler, M. Articles by Groettrup, M. PubMed PubMed Citation Articles by Basler, M. Articles by Groettrup, M.

The Proteasome Inhibitor Bortezomib Enhances the Susceptibility to Viral Infection¹

Michael Basler,^2* Christoph Lauer, Ulrike Beck, and Marcus Groettrup^*

^*Biotechnology Institute Thurgau (BITg) at Constance University, CH-8280 Kreuzlingen, Switzerland; and Division of Immunology, Department of Biology, University of Constance, Konstanz, Germany

The proteasome, a multicatalytic protease, is responsible for the generation of most MHC class I ligands. Bortezomib, a proteasome inhibitor, is clinically approved for treatment of multiple myeloma and mantle cell myeloma. In the present study, we investigated the effect of bortezomib on viral infection. Infection of bortezomib-treated mice with the lymphocytic choriomeningitis virus (LCMV) led to a decreased cytotoxic T cell response to several LCMV-derived CD8⁺ T cell epitopes. Bortezomib treatment caused a reduced expansion of CD8⁺ T lymphocytes and increased viral titers in LCMV-infected mice. Administration of bortezomib during expansion of CD8⁺ T cells had no influence on the cytotoxic T cell response, suggesting that bortezomib interferes with priming of naive T cells. Indeed, determination of Ag load in spleen 4 days post infection, revealed a reduced presentation of LCMV-derived cytotoxic T cell epitopes on MHC class I molecules. In summary, we show that proteasome inhibition with bortezomib led to an increased susceptibility to viral infection, and demonstrate for the first time, that proteasome inhibitors can alter Ag processing in vivo.

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 This work was funded by the German National Science Foundation (DFG) Grant Nr. GR1517/4-2.

² Address correspondence and reprint requests to: Dr. Michael Basler, Department of Biology, Division of Immunology, University of Constance, P1101 Universitätsstrasse 10, Konstanz, Germany. E-mail address: Michael.Basler{at}uni-konstanz.de

³ Abbreviations used in this paper: MHC-I, MHC class I; LCMV, lymphocytic choriomeningitis virus; GP, glycoprotein; NP, nucleoprotein; ICS, intracellular cytokine staining; DC, dendritic cell; VSV, vesicular stomatitis virus; NK, neutral killer; VZV, varicella zoster virus.