{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,3,21]],"date-time":"2026-03-21T18:56:51Z","timestamp":1774119411939,"version":"3.50.1"},"reference-count":50,"publisher":"Oxford University Press (OUP)","issue":"10","license":[{"start":{"date-parts":[[2009,11,1]],"date-time":"2009-11-01T00:00:00Z","timestamp":1257033600000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/academic.oup.com\/pages\/standard-publication-reuse-rights"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":[],"published-print":{"date-parts":[[2009,11,15]]},"abstract":"<jats:title>Abstract<\/jats:title>\n               <jats:p>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.<\/jats:p>","DOI":"10.4049\/jimmunol.0901596","type":"journal-article","created":{"date-parts":[[2009,10,20]],"date-time":"2009-10-20T01:31:56Z","timestamp":1256002316000},"page":"6145-6150","source":"Crossref","is-referenced-by-count":93,"title":["The Proteasome Inhibitor Bortezomib Enhances the Susceptibility to Viral Infection"],"prefix":"10.1093","volume":"183","author":[{"given":"Michael","family":"Basler","sequence":"first","affiliation":[{"name":"Biotechnology Institute Thurgau (BITg) at Constance University , CH-8280 Kreuzlingen,","place":["Switzerland"]},{"name":"Division of Immunology, Department of Biology, University of Constance , Konstanz,","place":["Germany"]}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Christoph","family":"Lauer","sequence":"additional","affiliation":[{"name":"Division of Immunology, Department of Biology, University of Constance , Konstanz,","place":["Germany"]}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Ulrike","family":"Beck","sequence":"additional","affiliation":[{"name":"Division of Immunology, Department of Biology, University of Constance , Konstanz,","place":["Germany"]}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Marcus","family":"Groettrup","sequence":"additional","affiliation":[{"name":"Biotechnology Institute Thurgau (BITg) at Constance University , CH-8280 Kreuzlingen,","place":["Switzerland"]},{"name":"Division of Immunology, Department of Biology, University of Constance , Konstanz,","place":["Germany"]}],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"286","published-online":{"date-parts":[[2009,11,15]]},"reference":[{"key":"2025032603222087900_R1","first-page":"7709","article-title":"Distinct 19 S and 20S subcomplexes of the 26 S proteasome and their distribution in the nucleus and the cytoplasm.","volume-title":"J. Biol. Chem.","year":"1994"},{"key":"2025032603222087900_R2","first-page":"463","article-title":"Structure of 20 S proteasome from yeast at 2.4A resolution.","volume-title":"Nature","year":"1997"},{"key":"2025032603222087900_R3","first-page":"22123","article-title":"The proteasome, a novel protease regulated by multiple mechanisms.","volume-title":"J. Biol. Chem.","year":"1999"},{"key":"2025032603222087900_R4","first-page":"367","article-title":"Interferon-\u03b3 inducible exchanges of 20S proteasome active site subunits: why?.","volume-title":"Biochimie","year":"2001"},{"key":"2025032603222087900_R5","first-page":"1652","article-title":"How proteolysis drives the cell cycle.","volume-title":"Science","year":"1996"},{"key":"2025032603222087900_R6","first-page":"303","article-title":"The role of the ubiquitin-proteasome pathway in apoptosis.","volume-title":"Cell Death Differ.","year":"1999"},{"key":"2025032603222087900_R7","first-page":"493","article-title":"The proteasome pathway is required for cytokine-induced endothelial-leukocyte adhesion molecule expression.","volume-title":"Immunity","year":"1995"},{"key":"2025032603222087900_R8","first-page":"1207","article-title":"Regulation of transcription factors by protein degradation.","volume-title":"Cell Mol. Life Sci.","year":"2000"},{"key":"2025032603222087900_R9","first-page":"243","article-title":"The proteasome is involved in angiogenesis.","volume-title":"Biochem. Biophys. Res. Commun.","year":"1998"},{"key":"2025032603222087900_R10","first-page":"29","article-title":"The specificity of proteasomes: impact on MHC class I processing and presentation of antigens.","volume-title":"Immunol. Rev.","year":"1999"},{"key":"2025032603222087900_R11","first-page":"1103","article-title":"The proteasome inhibitor lactacystin induces apoptosis and sensitizes chemo- and radioresistant human chronic lymphocytic leukaemia lymphocytes to TNF-\u03b1-initiated apoptosis.","volume-title":"Br. J. Cancer","year":"1998"},{"key":"2025032603222087900_R12","first-page":"4342","article-title":"Tumor growth inhibition induced in a murine model of human Burkitt\u2019s lymphoma by a proteasome inhibitor.","volume-title":"Cancer Res.","year":"1998"},{"key":"2025032603222087900_R13","first-page":"333","article-title":"Potent and selective inhibitors of the proteasome: dipeptidyl boronic acids.","volume-title":"Bioorg. Med. Chem. Lett.","year":"1998"},{"key":"2025032603222087900_R14","first-page":"2615","article-title":"Proteasome inhibitors: a novel class of potent and effective antitumor agents.","volume-title":"Cancer Res.","year":"1999"},{"key":"2025032603222087900_R15","first-page":"336","article-title":"The proteasome-specific inhibitor lactacystin blocks presentation of cytotoxic T lymphocyte epitopes in human and murine cells.","volume-title":"Eur. J. Immunol.","year":"1997"},{"key":"2025032603222087900_R16","first-page":"4859","article-title":"Dissociation of proteasomal degradation of biosynthesized viral proteins from generation of MHC class I-associated antigenic peptides.","volume-title":"J. Immunol.","year":"1998"},{"key":"2025032603222087900_R17","first-page":"581","article-title":"The proteasome inhibitor lactacystin prevents the generation of an endoplasmic reticulum leader-derived T cell epitope.","volume-title":"Mol. Immunol.","year":"1998"},{"key":"2025032603222087900_R18","first-page":"6147","article-title":"The selective proteasome inhibitors lactacystin and expoxomicin can be used to either up- or downregulate antigen presentation at non-toxic doses.","volume-title":"J. Immunol.","year":"2000"},{"key":"2025032603222087900_R19","first-page":"896","article-title":"No essential role for tripeptidyl peptidase II for the processing of LCMV-derived T cell epitopes.","volume-title":"Eur. J. Immunol.","year":"2007"},{"key":"2025032603222087900_R20","first-page":"1867","article-title":"Mechanism of recovery from acute virus infection: treatment of lymphocytic choriomeningits virus-infected mice with monoclonal antibodies reveals that Lyt-2+ T lymphocytes mediate clearance of virus and regulate the antiviral antibody response.","volume-title":"J. Virol.","year":"1987"},{"key":"2025032603222087900_R21","first-page":"5543","article-title":"Analysis of cytotoxic T cell responses to dominant and subdominant epitopes during acute and chronic lymphocytic choriomeningitis virus infection.","volume-title":"J. Immunol.","year":"1996"},{"key":"2025032603222087900_R22","first-page":"1647","article-title":"Protective immunity does not correlate with the hierarchy of virus-specific cytotoxic T cell responses to naturally processed peptides.","volume-title":"J. Exp. Med.","year":"1998"},{"key":"2025032603222087900_R23","first-page":"93","article-title":"Changing immunodominance patterns in antiviral CD8 T-cell responses after loss of epitope presentation or chronic antigenic stimulation.","volume-title":"Virology","year":"2003"},{"key":"2025032603222087900_R24","first-page":"191","article-title":"Quantification of lymphocytic choriomeningitis virus with an immunological focus assay in 24- or 96-well plates.","volume-title":"J. Virol. Methods","year":"1991"},{"key":"2025032603222087900_R25","first-page":"6665","article-title":"An altered T cell repertoire in MECL-1-deficient mice.","volume-title":"J. Immunol.","year":"2006"},{"key":"2025032603222087900_R26","first-page":"3925","article-title":"Immunoproteasomes down-regulate presentation of a subdominant T cell epitope from lymphocytic choriomeningitis virus.","volume-title":"J. Immunol.","year":"2004"},{"key":"2025032603222087900_R27","first-page":"2505","article-title":"A phase I trial of the novel proteasome inhibitor PS341 in advanced solid tumor malignancies.","volume-title":"Clin. Cancer Res.","year":"2002"},{"key":"2025032603222087900_R28","first-page":"4420","article-title":"Phase I trial of the proteasome inhibitor PS-341 in patients with refractory hematologic malignancies.","volume-title":"J. Clin. Oncol.","year":"2002"},{"key":"2025032603222087900_R29","first-page":"4996","article-title":"Proteasome inhibitor PS-341 inhibits human myeloma cell growth in vivo and prolongs survival in a murine model.","volume-title":"Cancer Res.","year":"2002"},{"key":"2025032603222087900_R30","first-page":"620","article-title":"In vivo state of antiviral CTL precursors: characterization of a cycling cell population containing CTL precursors in immune mice.","volume-title":"J. Immunol.","year":"1995"},{"key":"2025032603222087900_R31","first-page":"177","article-title":"Counting antigen-specific CD8 T cells: a reevaluation of bystander activation during viral infection.","volume-title":"Immunity","year":"1998"},{"key":"2025032603222087900_R32","first-page":"8407","article-title":"Critical role for \u03b1\/\u03b2 and \u03b3 interferons in persistence of lymphocytic choriomeningitis virus by clonal exhaustion of cytotoxic T cells.","volume-title":"J. Virol.","year":"2001"},{"key":"2025032603222087900_R33","first-page":"3575","article-title":"Bortezomib induces selective depletion of alloreactive T lymphocytes and decreases the production of Th1 cytokines.","volume-title":"Blood","year":"2006"},{"key":"2025032603222087900_R34","first-page":"51","article-title":"Immunodominance in major histocompatibility complex class I- restricted T lymphocyte responses.","volume-title":"Annu. Rev. Immunol.","year":"1999"},{"key":"2025032603222087900_R35","first-page":"2071","article-title":"Both dendritic cells and macrophages can stimulate naive CD8 T cells in vivo to proliferate, develop effector function, and differentiate into memory cells.","volume-title":"J. Immunol.","year":"2005"},{"key":"2025032603222087900_R36","first-page":"681","article-title":"Proteasome inhibitor-induced apoptosis in human monocyte-derived dendritic cells.","volume-title":"Eur. J. Immunol.","year":"2006"},{"key":"2025032603222087900_R37","first-page":"234","article-title":"Proteasome inhibition suppresses essential immune functions of human CD4+ T cells.","volume-title":"Immunology","year":"2008"},{"key":"2025032603222087900_R38","first-page":"147","article-title":"Dendritic cell maturation stage determines susceptibility to the proteasome inhibitor bortezomib.","volume-title":"Hum. Immunol.","year":"2007"},{"key":"2025032603222087900_R39","first-page":"600","article-title":"Proteasome inhibition drastically but reversibly impairs murine lymphocyte development.","volume-title":"Cell Death Differ.","year":"2008"},{"key":"2025032603222087900_R40","first-page":"e1887","article-title":"Different effect of proteasome inhibition on vesicular stomatitis virus and poliovirus replication.","volume-title":"PLoS ONE.","year":"2008"},{"key":"2025032603222087900_R41","first-page":"2099","article-title":"Orthopoxviruses require a functional ubiquitin-proteasome system for productive replication.","volume-title":"J. Virol.","year":"2009"},{"key":"2025032603222087900_R42","first-page":"1464","article-title":"Bortezomib significantly impairs the immunostimulatory capacity of human myeloid blood dendritic cells.","volume-title":"Leukemia","year":"2007"},{"key":"2025032603222087900_R43","first-page":"761","article-title":"Inhibitors of the proteasome block the degradation of most cell proteins and the generation of peptides presented on MHC class I molecules.","volume-title":"Cell","year":"1994"},{"key":"2025032603222087900_R44","first-page":"3678","article-title":"Rapid peptide turnover and inefficient presentation of exogenous antigen critically limit the activation of self-reactive CTL by dendritic cells.","volume-title":"J. Immunol.","year":"2001"},{"key":"2025032603222087900_R45","first-page":"1309","article-title":"Bortezomib down-regulates the cell-surface expression of HLA class I and enhances natural killer cell-mediated lysis of myeloma.","volume-title":"Blood","year":"2008"},{"key":"2025032603222087900_R46","first-page":"330","article-title":"Bortezomib in combination with intermediate-dose dexamethasone and continuous low-dose oral cyclophosphamide for relapsed multiple myeloma.","volume-title":"Br. J. Haematol.","year":"2007"},{"key":"2025032603222087900_R47","first-page":"301","article-title":"Late onset of bortezomib-associated cutaneous reaction following herpes zoster.","volume-title":"Ann. Hematol.","year":"2007"},{"key":"2025032603222087900_R48","first-page":"403","article-title":"The high incidence of varicella herpes zoster with the use of bortezomib in 10 patients.","volume-title":"Am. J. Hematol.","year":"2007"},{"key":"2025032603222087900_R49","first-page":"4784","article-title":"Analysis of herpes zoster events among bortezomib-treated patients in the phase III APEX study.","volume-title":"J. Clin. Oncol.","year":"2008"},{"key":"2025032603222087900_R50","first-page":"40","article-title":"Identification of CD8+ T cell epitopes in the immediate early 62 protein (IE62) of varicella-zoster virus, and evaluation of frequency of CD8+ T cell response to IE62, by use of IE62 peptides after varicella vaccination.","volume-title":"J. Infect. Dis.","year":"2003"}],"container-title":["The Journal of Immunology"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/academic.oup.com\/jimmunol\/article-pdf\/183\/10\/6145\/62695252\/9947.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"syndication"},{"URL":"https:\/\/academic.oup.com\/jimmunol\/article-pdf\/183\/10\/6145\/62695252\/9947.pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,3,29]],"date-time":"2025-03-29T09:58:17Z","timestamp":1743242297000},"score":1,"resource":{"primary":{"URL":"https:\/\/academic.oup.com\/jimmunol\/article\/183\/10\/6145\/8053505"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2009,11]]},"references-count":50,"journal-issue":{"issue":"10","published-print":{"date-parts":[[2009,11,15]]}},"URL":"https:\/\/doi.org\/10.4049\/jimmunol.0901596","relation":{},"ISSN":["1550-6606","0022-1767"],"issn-type":[{"value":"1550-6606","type":"electronic"},{"value":"0022-1767","type":"print"}],"subject":[],"published-other":{"date-parts":[[2009,11]]},"published":{"date-parts":[[2009,11]]}}}