{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,21]],"date-time":"2026-10-21T08:46:51Z","timestamp":1792572411078,"version":"4.5.0"},"reference-count":55,"publisher":"Rockefeller University Press","issue":"9","content-domain":{"domain":["rupress.org"],"crossmark-restriction":true},"short-container-title":[],"published-print":{"date-parts":[[1997,5,5]]},"abstract":"<jats:p>Epstein-Barr virus (EBV), a human \u03b3-herpesvirus, can establish both nonproductive (latent) and productive (lytic) infections. Although the CD8+ cytotoxic T lymphocyte (CTL) response to latently infected cells is well characterized, very little is known about T cell controls over lytic infection; this imbalance in our understanding belies the importance of virus-replicative lesions in several aspects of EBV disease pathogenesis. The present work shows that the primary CD8+ CTL response to EBV in infectious mononucleosis patients contains multiple lytic antigen-specific reactivities at levels at least as high as those seen against latent antigens; similar reactivities are also detectable in CTL memory. Clonal analysis revealed individual responses to the two immediate early proteins BZLF1 and BRLF1, and to three (BMLF1, BMRF1, and BALF2) of the six early proteins tested. In several cases, the peptide epitope and HLA-restricting determinant recognized by these CTLs has been defined, one unusual feature being the number of responses restricted through HLA-C alleles. The work strongly suggests that EBVreplicative lesions are subject to direct CTL control in vivo and that immediate early and early proteins are frequently the immunodominant targets. This contrasts with findings in \u03b1- and \u03b2-herpesvirus systems (herpes simplex, cytomegalovirus) where viral interference with the antigen-processing pathway during lytic infection renders immediate early and early proteins much less immunogenic. The unique capacity of \u03b3-herpesvirus to amplify the viral load in vivo through a latent growth-transforming infection may have rendered these agents less dependent upon viral replication as a means of successfully colonizing their hosts.<\/jats:p>","DOI":"10.1084\/jem.185.9.1605","type":"journal-article","created":{"date-parts":[[2002,7,26]],"date-time":"2002-07-26T16:49:30Z","timestamp":1027702170000},"page":"1605-1618","update-policy":"https:\/\/doi.org\/10.1084\/jem.crossmarkpolicy","source":"Crossref","is-referenced-by-count":268,"title":["Immediate Early and Early Lytic Cycle Proteins Are Frequent Targets of the Epstein-Barr Virus\u2013induced Cytotoxic T Cell Response"],"prefix":"10.1084","volume":"185","author":[{"given":"N.M.","family":"Steven","sequence":"first","affiliation":[{"name":"From the *Cancer Research Campaign Institute for Cancer Studies, University of Birmingham, Birmingham, B15 2TT, U.K.; and the \u2021Department of Pathology, University of Virginia, Charlottesville, Virginia 22908"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"N.E.","family":"Annels","sequence":"additional","affiliation":[{"name":"From the *Cancer Research Campaign Institute for Cancer Studies, University of Birmingham, Birmingham, B15 2TT, U.K.; and the \u2021Department of Pathology, University of Virginia, Charlottesville, Virginia 22908"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"A.","family":"Kumar","sequence":"additional","affiliation":[{"name":"From the *Cancer Research Campaign Institute for Cancer Studies, University of Birmingham, Birmingham, B15 2TT, U.K.; and the \u2021Department of Pathology, University of Virginia, Charlottesville, Virginia 22908"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"A.M.","family":"Leese","sequence":"additional","affiliation":[{"name":"From the *Cancer Research Campaign Institute for Cancer Studies, University of Birmingham, Birmingham, B15 2TT, U.K.; and the \u2021Department of Pathology, University of Virginia, Charlottesville, Virginia 22908"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"M.G.","family":"Kurilla","sequence":"additional","affiliation":[{"name":"From the *Cancer Research Campaign Institute for Cancer Studies, University of Birmingham, Birmingham, B15 2TT, U.K.; and the \u2021Department of Pathology, University of Virginia, Charlottesville, Virginia 22908"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"A.B.","family":"Rickinson","sequence":"additional","affiliation":[{"name":"From the *Cancer Research Campaign Institute for Cancer Studies, University of Birmingham, Birmingham, B15 2TT, U.K.; and the \u2021Department of Pathology, University of Virginia, Charlottesville, Virginia 22908"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"291","published-online":{"date-parts":[[1997,5,5]]},"reference":[{"key":"2023072915222363800_B1"},{"key":"2023072915222363800_B2","doi-asserted-by":"crossref","first-page":"1225","DOI":"10.1056\/NEJM198405103101905","article-title":"Epstein-Barr virus replication in oropharyngeal epithelial cells","volume":"310","author":"Sixbey","year":"1984","journal-title":"N Engl J Med"},{"key":"2023072915222363800_B3","doi-asserted-by":"crossref","first-page":"744","DOI":"10.1182\/blood.V85.3.744.bloodjournal853744","article-title":"Morphology, immunophenotype and distribution of latently and\/or productively Epstein-Barr virus\u2013infected cells in acute infectious mononucleosis: implications for the interindividual infection route of Epstein-Barr virus","volume":"85","author":"Anagnostopoulos","year":"1995","journal-title":"Blood"},{"key":"2023072915222363800_B4","doi-asserted-by":"crossref","first-page":"7374","DOI":"10.1128\/jvi.68.11.7374-7385.1994","article-title":"Epstein-Barr virus latency in blood mononuclear cells: analysis of viral gene transcription during primary infection and in the carrier state","volume":"68","author":"Tierney","year":"1994","journal-title":"J Virol"},{"key":"2023072915222363800_B5","doi-asserted-by":"crossref","first-page":"67","DOI":"10.1002\/ijc.2910430115","article-title":"Epstein-Barr virus\u2013infected B cells persist in the circulation of acyclovir-treated virus carriers","volume":"43","author":"Yao","year":"1989","journal-title":"Int J Cancer"},{"key":"2023072915222363800_B6","doi-asserted-by":"crossref","first-page":"593","DOI":"10.1016\/0092-8674(95)90513-8","article-title":"A novel form of Epstein-Barr virus latency in normal B cells in vivo","volume":"80","author":"Miyashita","year":"1995","journal-title":"Cell"},{"key":"2023072915222363800_B7","doi-asserted-by":"crossref","first-page":"1801","DOI":"10.1084\/jem.184.5.1801","article-title":"Epitope focusing in the primary cytotoxic T cell response to Epstein-Barr virus and its relationship to T cell memory","volume":"184","author":"Steven","year":"1996","journal-title":"J Exp Med"},{"key":"2023072915222363800_B8","doi-asserted-by":"crossref","first-page":"157","DOI":"10.1084\/jem.176.1.157","article-title":"Identification of target antigens for the human cytotoxic T cell response to Epstein-Barr virus (EBV): implications for the immune control of EBV-positive malignancies","volume":"176","author":"Murray","year":"1992","journal-title":"J Exp Med"},{"key":"2023072915222363800_B9","doi-asserted-by":"crossref","first-page":"169","DOI":"10.1084\/jem.176.1.169","article-title":"Localization of Epstein-Barr virus cytotoxic T cell epitopes using recombinant vaccinia: implications for vaccine development","volume":"176","author":"Khanna","year":"1992","journal-title":"J Exp Med"},{"key":"2023072915222363800_B10","doi-asserted-by":"crossref","first-page":"1564","DOI":"10.1056\/NEJM198512193132502","article-title":"Replication of Epstein-Barr virus within the epithelial cells of oral \u201chairy\u201d leukoplakia, an AIDS-associated lesion","volume":"313","author":"Greenspan","year":"1985","journal-title":"N Engl J Med"},{"key":"2023072915222363800_B11","doi-asserted-by":"crossref","first-page":"1390","DOI":"10.1016\/S0140-6736(85)92557-7","article-title":"Opportunistic lymphoproliferations associated with Epstein-Barr viral DNA in infants and children with AIDS","volume":"ii","author":"Andiman","year":"1985","journal-title":"Lancet"},{"key":"2023072915222363800_B12","doi-asserted-by":"crossref","first-page":"3350","DOI":"10.1182\/blood.V81.12.3350.3350","article-title":"Epstein-Barr virus\u2013related oral T cell lymphoma associated with human immunodeficiency virus immunosuppression","volume":"81","author":"Thomas","year":"1993","journal-title":"Blood"},{"key":"2023072915222363800_B13","doi-asserted-by":"crossref","first-page":"1234","DOI":"10.1136\/thx.50.12.1234","article-title":"Epstein-Barr virus replication within pulmonary epithelial cells in cryptogenic fibrosing alveolitis","volume":"50","author":"Egan","year":"1995","journal-title":"Thorax"},{"key":"2023072915222363800_B14","doi-asserted-by":"crossref","first-page":"919","DOI":"10.1084\/jem.168.3.919","article-title":"Human cytomegalovirus\u2013specific cytotoxic T cells. 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