{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,2,2]],"date-time":"2026-02-02T19:48:54Z","timestamp":1770061734923,"version":"3.49.0"},"reference-count":33,"publisher":"Oxford University Press (OUP)","issue":"8","content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":[],"published-print":{"date-parts":[[2010,4,15]]},"abstract":"<jats:title>Abstract<\/jats:title>\n               <jats:p>The generation of a robust CD8+ T cell response is an ongoing challenge for the development of DNA vaccines. One problem encountered with classical DNA plasmid immunization is that peptides produced are noncovalently and transiently associated with MHC class I molecules and thus may not durably stimulate CD8+ T cell responses. To address this and enhance the expression and presentation of the antigenic peptide\/MHC complexes, we generated single-chain trimers (SCTs) composed of a single polypeptide chain with a linear composition of antigenic peptide, \u03b22-microglobulin, and H chain connected by flexible linkers. In this study, we test whether the preassembled nature of the SCT makes them effective for eliciting protective CD8+ T cell responses against pathogens. A DNA plasmid was constructed encoding an SCT incorporating the human MHC class I molecule HLA-A2 and the immunodominant peptide SVG9 derived from the envelope protein of West Nile virus (WNV). HLA-A2 transgenic mice vaccinated with the DNA encoding the SVG9\/HLA-A2 SCT generated a robust epitope-specific CD8+ T cell response and showed enhanced survival rate and lower viral burden in the brain after lethal WNV challenge. Inclusion of a CD4+ Th cell epitope within the SCT did not increase the frequency of SVG9-specific CD8+ T cells, but did enhance protection against WNV challenge. Overall, these findings demonstrate that the SCT platform can induce protective CD8+ T cell responses against lethal virus infection and may be paired with immunogens that elicit robust neutralizing Ab responses to generate vaccines that optimally activate all facets of adaptive immunity.<\/jats:p>","DOI":"10.4049\/jimmunol.0903955","type":"journal-article","created":{"date-parts":[[2010,3,9]],"date-time":"2010-03-09T05:19:17Z","timestamp":1268111957000},"page":"4423-4430","source":"Crossref","is-referenced-by-count":46,"title":["Single-Chain HLA-A2 MHC Trimers That Incorporate an Immundominant Peptide Elicit Protective T Cell Immunity against Lethal West Nile Virus Infection"],"prefix":"10.1093","volume":"184","author":[{"given":"Sojung","family":"Kim","sequence":"first","affiliation":[{"name":"*Department of Pathology and Immunology,"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Lijin","family":"Li","sequence":"additional","affiliation":[{"name":"\u2020Department of Surgery,"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Curtis P.","family":"McMurtrey","sequence":"additional","affiliation":[{"name":"\u2021Department of Microbiology and Immunology, University of Oklahoma Health Sciences Center, Oklahoma City, OK 73104;"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"William H.","family":"Hildebrand","sequence":"additional","affiliation":[{"name":"\u2021Department of Microbiology and Immunology, University of Oklahoma Health Sciences Center, Oklahoma City, OK 73104;"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Jon A.","family":"Weidanz","sequence":"additional","affiliation":[{"name":"\u00a7Receptor Logic, Inc., Austin, TX 78738; and"},{"name":"\u00b6Department of Pharmaceutical Sciences, School of Pharmacy, Center for Immunotherapeutic Research, Texas Tech University Health Sciences Center, Abilene, TX 79601"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"William E.","family":"Gillanders","sequence":"additional","affiliation":[{"name":"\u2020Department of Surgery,"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Michael S.","family":"Diamond","sequence":"additional","affiliation":[{"name":"*Department of Pathology and Immunology,"},{"name":"\u2016Department of Medicine,"},{"name":"#Department of Molecular Microbiology, and"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Ted H.","family":"Hansen","sequence":"additional","affiliation":[{"name":"*Department of Pathology and Immunology,"},{"name":"**Department of Genetics, Washington University School of Medicine, St. Louis, MO 63110;"}],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"286","published-online":{"date-parts":[[2010,4,15]]},"reference":[{"key":"2023010203072559000_r1","doi-asserted-by":"crossref","first-page":"519","DOI":"10.1146\/annurev.immunol.23.021704.115825","article-title":"Cooperation between CD4+ and CD8+ T cells: when, where, and how.","volume":"24","author":"Castellino","year":"2006","journal-title":"Annu. Rev. Immunol."},{"key":"2023010203072559000_r2","doi-asserted-by":"crossref","first-page":"1507","DOI":"10.4049\/jimmunol.158.4.1507","article-title":"MHC affinity, peptide liberation, T cell repertoire, and immunodominance all contribute to the paucity of MHC class I-restricted peptides recognized by antiviral CTL.","volume":"158","author":"Deng","year":"1997","journal-title":"J. Immunol."},{"key":"2023010203072559000_r3","doi-asserted-by":"crossref","first-page":"3145","DOI":"10.4049\/jimmunol.168.7.3145","article-title":"Cutting edge: single-chain trimers of MHC class I molecules form stable structures that potently stimulate antigen-specific T cells and B cells.","volume":"168","author":"Yu","year":"2002","journal-title":"J. Immunol."},{"key":"2023010203072559000_r4","doi-asserted-by":"crossref","first-page":"125","DOI":"10.1016\/S0022-1759(02)00346-0","article-title":"Peptide-beta2-microglobulin-MHC fusion molecules bind antigen-specific T cells and can be used for multivalent MHC-Ig complexes.","volume":"271","author":"Greten","year":"2002","journal-title":"J. Immunol. Methods"},{"key":"2023010203072559000_r5","doi-asserted-by":"crossref","first-page":"578","DOI":"10.1038\/nature03843","article-title":"T-cell receptor triggering is critically dependent on the dimensions of its peptide-MHC ligand.","volume":"436","author":"Choudhuri","year":"2005","journal-title":"Nature"},{"key":"2023010203072559000_r6","article-title":"Preparation of stable single-chain trimers engineered with peptide, beta2 microglobulin, and MHC heavy chain","volume-title":"Curr. Protoc. Immunol.","author":"Hansen","year":"2009"},{"key":"2023010203072559000_r7","doi-asserted-by":"crossref","first-page":"1180","DOI":"10.1038\/sj.gt.3302519","article-title":"Cancer immunotherapy using a DNA vaccine encoding a single-chain trimer of MHC class I linked to an HPV-16 E6 immunodominant CTL epitope.","volume":"12","author":"Huang","year":"2005","journal-title":"Gene Ther."},{"key":"2023010203072559000_r8","doi-asserted-by":"crossref","first-page":"4565","DOI":"10.4049\/jimmunol.0803893","article-title":"A single-chain H-2Db molecule presenting an influenza virus nucleoprotein epitope shows enhanced ability at stimulating CD8+ T cell responses in vivo.","volume":"182","author":"Palmowski","year":"2009","journal-title":"J. Immunol."},{"key":"2023010203072559000_r9","doi-asserted-by":"crossref","first-page":"109","DOI":"10.1385\/IR:32:1-3:109","article-title":"Applications of major histocompatibility complex class I molecules expressed as single chains.","volume":"32","author":"Primeau","year":"2005","journal-title":"Immunol. Res."},{"key":"2023010203072559000_r10","doi-asserted-by":"crossref","first-page":"29","DOI":"10.1007\/s10549-004-8918-1","article-title":"Recognition of HLA-A2-restricted mammaglobin-A-derived epitopes by CD8+ cytotoxic T lymphocytes from breast cancer patients.","volume":"88","author":"Jaramillo","year":"2004","journal-title":"Breast Cancer Res. Treat."},{"key":"2023010203072559000_r11","doi-asserted-by":"crossref","first-page":"105","DOI":"10.1111\/j.1365-2567.2007.02543.x","article-title":"Hepatitis B virus core antigen epitopes presented by HLA-A2 single-chain trimers induce functional epitope-specific CD8+ T-cell responses in HLA-A2.1\/Kb transgenic mice.","volume":"121","author":"Zhang","year":"2007","journal-title":"Immunology"},{"key":"2023010203072559000_r12","doi-asserted-by":"crossref","first-page":"1807","DOI":"10.1056\/NEJM200106143442401","article-title":"The outbreak of West Nile virus infection in the New York City area in 1999.","volume":"344","author":"Nash","year":"2001","journal-title":"N. Engl. J. Med."},{"key":"2023010203072559000_r13","doi-asserted-by":"crossref","first-page":"259","DOI":"10.1089\/088282403322396082","article-title":"Innate and adaptive immune responses determine protection against disseminated infection by West Nile encephalitis virus.","volume":"16","author":"Diamond","year":"2003","journal-title":"Viral Immunol."},{"key":"2023010203072559000_r14","doi-asserted-by":"crossref","first-page":"2020","DOI":"10.1016\/j.vaccine.2008.02.009","article-title":"The relative contribution of antibody and CD8+ T cells to vaccine immunity against West Nile encephalitis virus.","volume":"26","author":"Shrestha","year":"2008","journal-title":"Vaccine"},{"key":"2023010203072559000_r15","doi-asserted-by":"crossref","first-page":"2981","DOI":"10.1073\/pnas.0711874105","article-title":"Epitope discovery in West Nile virus infection: Identification and immune recognition of viral epitopes.","volume":"105","author":"McMurtrey","year":"2008","journal-title":"Proc. Natl. Acad. Sci. USA"},{"key":"2023010203072559000_r16","doi-asserted-by":"crossref","first-page":"1845","DOI":"10.1002\/eji.200737192","article-title":"Antigen-specific cytotoxic T lymphocytes protect against lethal West Nile virus encephalitis.","volume":"37","author":"Purtha","year":"2007","journal-title":"Eur. J. Immunol."},{"key":"2023010203072559000_r17","doi-asserted-by":"crossref","first-page":"2043","DOI":"10.1084\/jem.185.12.2043","article-title":"HLA-A2.1-restricted education and cytolytic activity of CD8(+) T lymphocytes from beta2 microglobulin (beta2m) HLA-A2.1 monochain transgenic H-2Db beta2m double knockout mice.","volume":"185","author":"Pascolo","year":"1997","journal-title":"J. Exp. Med."},{"key":"2023010203072559000_r18","doi-asserted-by":"crossref","first-page":"2578","DOI":"10.1128\/JVI.77.4.2578-2586.2003","article-title":"B cells and antibody play critical roles in the immediate defense of disseminated infection by West Nile encephalitis virus.","volume":"77","author":"Diamond","year":"2003","journal-title":"J. Virol."},{"key":"2023010203072559000_r19","doi-asserted-by":"crossref","first-page":"3112","DOI":"10.1002\/(SICI)1521-4141(199910)29:10<3112::AID-IMMU3112>3.0.CO;2-Q","article-title":"H-2 class I knockout, HLA-A2.1-transgenic mice: a versatile animal model for preclinical evaluation of antitumor immunotherapeutic strategies.","volume":"29","author":"Firat","year":"1999","journal-title":"Eur. J. Immunol."},{"key":"2023010203072559000_r20","doi-asserted-by":"crossref","first-page":"2187","DOI":"10.1084\/jem.20070489","article-title":"Cross-competition of CD8+ T cells shapes the immunodominance hierarchy during boost vaccination.","volume":"204","author":"Kastenmuller","year":"2007","journal-title":"J. Exp. Med."},{"key":"2023010203072559000_r21","doi-asserted-by":"crossref","first-page":"560","DOI":"10.1046\/j.1523-1747.2000.00904.x","article-title":"Langerhans cells migrate to local lymph nodes following cutaneous infection with an arbovirus.","volume":"114","author":"Johnston","year":"2000","journal-title":"J. Invest. Dermatol."},{"key":"2023010203072559000_r22","doi-asserted-by":"crossref","first-page":"8312","DOI":"10.1128\/JVI.78.15.8312-8321.2004","article-title":"Role of CD8+ T cells in control of West Nile virus infection.","volume":"78","author":"Shrestha","year":"2004","journal-title":"J. Virol."},{"key":"2023010203072559000_r23","doi-asserted-by":"crossref","first-page":"1211","DOI":"10.1038\/sj.mt.6300121","article-title":"DNA vaccines encoding Ii-PADRE generates potent PADRE-specific CD4+ T-cell immune responses and enhances vaccine potency.","volume":"15","author":"Hung","year":"2007","journal-title":"Mol. Ther."},{"key":"2023010203072559000_r24","doi-asserted-by":"crossref","first-page":"899","DOI":"10.1038\/nm1264","article-title":"A rapid and potent DNA vaccination strategy defined by in vivo monitoring of antigen expression.","volume":"11","author":"Bins","year":"2005","journal-title":"Nat. Med."},{"key":"2023010203072559000_r25","doi-asserted-by":"crossref","first-page":"522","DOI":"10.1038\/nm1240","article-title":"Development of a humanized monoclonal antibody with therapeutic potential against West Nile virus.","volume":"11","author":"Oliphant","year":"2005","journal-title":"Nat. Med."},{"key":"2023010203072559000_r26","doi-asserted-by":"crossref","first-page":"11828","DOI":"10.1128\/JVI.00643-07","article-title":"Induction of epitope-specific neutralizing antibodies against West Nile virus.","volume":"81","author":"Oliphant","year":"2007","journal-title":"J. Virol."},{"key":"2023010203072559000_r27","doi-asserted-by":"crossref","first-page":"776","DOI":"10.1038\/nrg2432","article-title":"DNA vaccines: ready for prime time?","volume":"9","author":"Kutzler","year":"2008","journal-title":"Nat. Rev. Genet."},{"key":"2023010203072559000_r28","doi-asserted-by":"crossref","first-page":"7480","DOI":"10.1074\/jbc.M709935200","article-title":"Human major histocompatibility complex (MHC) class I molecules with disulfide traps secure disease-related antigenic peptides and exclude competitor peptides.","volume":"283","author":"Truscott","year":"2008","journal-title":"J. Biol. Chem."},{"key":"2023010203072559000_r29","doi-asserted-by":"crossref","first-page":"503","DOI":"10.1038\/nri2575","article-title":"MHC class I antigen presentation: learning from viral evasion strategies.","volume":"9","author":"Hansen","year":"2009","journal-title":"Nat. Rev. Immunol."},{"key":"2023010203072559000_r30","doi-asserted-by":"crossref","first-page":"12060","DOI":"10.1128\/JVI.01650-06","article-title":"CD4+ T-cell responses are required for clearance of West Nile virus from the central nervous system.","volume":"80","author":"Sitati","year":"2006","journal-title":"J. Virol."},{"key":"2023010203072559000_r31","doi-asserted-by":"crossref","first-page":"1855","DOI":"10.1002\/eji.200737196","article-title":"Protective capacity and epitope specificity of CD8(+) T cells responding to lethal West Nile virus infection.","volume":"37","author":"Brien","year":"2007","journal-title":"Eur. J. Immunol."},{"key":"2023010203072559000_r32","doi-asserted-by":"crossref","first-page":"1555","DOI":"10.1084\/jem.184.4.1555","article-title":"Gene vaccination with naked plasmid DNA: mechanism of CTL priming.","volume":"184","author":"Corr","year":"1996","journal-title":"J. Exp. Med."},{"key":"2023010203072559000_r33","doi-asserted-by":"crossref","first-page":"9519","DOI":"10.1073\/pnas.91.20.9519","article-title":"Intradermal gene immunization: the possible role of DNA uptake in the induction of cellular immunity to viruses.","volume":"91","author":"Raz","year":"1994","journal-title":"Proc. Natl. Acad. Sci. USA"}],"container-title":["The Journal of Immunology"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/journals.aai.org\/jimmunol\/article-pdf\/184\/8\/4423\/1324379\/ji_0903955.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"syndication"},{"URL":"https:\/\/journals.aai.org\/jimmunol\/article-pdf\/184\/8\/4423\/1324379\/ji_0903955.pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,1,2]],"date-time":"2025-01-02T17:57:20Z","timestamp":1735840640000},"score":1,"resource":{"primary":{"URL":"https:\/\/journals.aai.org\/jimmunol\/article\/184\/8\/4423\/82445\/Single-Chain-HLA-A2-MHC-Trimers-That-Incorporate"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2010,4,15]]},"references-count":33,"journal-issue":{"issue":"8","published-online":{"date-parts":[[2010,4,15]]},"published-print":{"date-parts":[[2010,4,15]]}},"URL":"https:\/\/doi.org\/10.4049\/jimmunol.0903955","relation":{},"ISSN":["0022-1767","1550-6606"],"issn-type":[{"value":"0022-1767","type":"print"},{"value":"1550-6606","type":"electronic"}],"subject":[],"published":{"date-parts":[[2010,4,15]]}}}