The proteasome inhibitor bortezomib enhances the susceptibility to viral infection.
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.
Biotechnology Institute Thurgau (BITg) at Constance University, CH-8280 Kreuzlingen, Switzerland. Michael.Basler@uni-konstanz.de
Michael
M
Basler
Christoph
C
Lauer
Ulrike
U
Beck
Marcus
M
Groettrup
D000818:Animals; D000970:Antineoplastic Agents / Q000009:adverse effects* / Q000494:pharmacology; D001897:Boronic Acids / Q000009:adverse effects* / Q000494:pharmacology; D000069286:Bortezomib; D018414:CD8-Positive T-Lymphocytes / Q000187:drug effects / Q000276:immunology* / Q000378:metabolism / Q000821:virology; D045744:Cell Line, Tumor; D003602:Cytotoxicity, Immunologic / Q000187:drug effects / Q000276:immunology; D000939:Epitopes / Q000276:immunology; D007371:Interferon-gamma / Q000276:immunology / Q000378:metabolism; D008216:Lymphocytic Choriomeningitis / Q000276:immunology* / Q000821:virology; D008217:Lymphocytic choriomeningitis virus / Q000276:immunology; D051379:Mice; D008810:Mice, Inbred C57BL; D010455:Peptides / Q000276:immunology / Q000378:metabolism; D011480:Protease Inhibitors / Q000009:adverse effects* / Q000494:pharmacology; D046988:Proteasome Endopeptidase Complex / Q000276:immunology / Q000378:metabolism; D061988:Proteasome Inhibitors; D011719:Pyrazines / Q000009:adverse effects* / Q000494:pharmacology
D000970:Antineoplastic Agents; D001897:Boronic Acids; D000939:Epitopes; D010455:Peptides; D011480:Protease Inhibitors; D061988:Proteasome Inhibitors; D011719:Pyrazines; D000069286:Bortezomib; D007371:Interferon-gamma; D046988:Proteasome Endopeptidase Complex