{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,8,18]],"date-time":"2026-08-18T01:33:58Z","timestamp":1787016838874,"version":"build-2736575974"},"reference-count":94,"publisher":"American Society for Microbiology","issue":"8","license":[{"start":{"date-parts":[[2025,8,19]],"date-time":"2025-08-19T00:00:00Z","timestamp":1755561600000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"},{"start":{"date-parts":[[2025,8,19]],"date-time":"2025-08-19T00:00:00Z","timestamp":1755561600000},"content-version":"tdm","delay-in-days":0,"URL":"https:\/\/journals.asm.org\/non-commercial-tdm-license"}],"funder":[{"DOI":"10.13039\/100000002","name":"National Institutes of Health","doi-asserted-by":"publisher","award":["R01 AI018757-34, R01 AI018757-35, R01 CA189806"],"award-info":[{"award-number":["R01 AI018757-34, R01 AI018757-35, R01 CA189806"]}],"id":[{"id":"10.13039\/100000002","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":["journals.asm.org"],"crossmark-restriction":true},"short-container-title":["J Virol"],"published-print":{"date-parts":[[2025,8,19]]},"abstract":"<jats:title>ABSTRACT<\/jats:title>\n                  <jats:sec>\n                    <jats:title\/>\n                    <jats:p>\n                      The germinal center model (GCM) of Epstein-Barr virus (EBV) persistence in humans proposes that EBV infects and drives na\u00efve B cells through the GC to establish a quiescent lifelong persistent infection in memory B cells. EBV causes several cancers, and the normal\n                      <jats:italic toggle=\"yes\">in vivo<\/jats:italic>\n                      counterparts of major EBV-associated cancers have been identified in the GCM. Yet, the normal\n                      <jats:italic toggle=\"yes\">in vivo<\/jats:italic>\n                      counterparts of immunosuppression-related\/immunoblastic B-cell lymphoma (IL), which occurs in immunosuppressed transplant and HIV patients and resembles lymphoblastoid cell lines (LCLs), remain elusive. We performed a comparative analysis of human tonsillar B cells to identify the closest normal\n                      <jats:italic toggle=\"yes\">in vivo<\/jats:italic>\n                      counterparts of ILs\/LCLs. Here we show that EBV-infected tonsillar marginal zone (MZ) B cells, which are GC-independent, are the closest\n                      <jats:italic toggle=\"yes\">in vivo<\/jats:italic>\n                      correlates of ILs\/LCLs. Like LCLs, EBV-infected MZ B cells express the EBV growth program, which includes high expression of the oncogenic LMP1 and the DNA-mutating enzyme activation-induced cytidine deaminase (AID), in the absence of the transcription factor BCL6. Furthermore, these EBV-infected MZ B cells are proliferating extensively and are Ki67\n                      <jats:sup>+<\/jats:sup>\n                      . AID expression, rapid proliferation, and LMP1 expression put these cells at high risk for tumor development. Of therapeutic importance, the high expression of LMP1 could prove to be the Achilles\u2019 heel of IL\/LCL-like EBV-infected MZ B cells to be targeted. Consequently, we now propose that there are two pathways of EBV persistence\n                      <jats:italic toggle=\"yes\">in vivo<\/jats:italic>\n                      : (i) the established GC model and (ii) the GC-independent MZ model, and EBV-infected MZ B cells are plausibly the\n                      <jats:italic toggle=\"yes\">in vivo<\/jats:italic>\n                      precursors of IL.\n                    <\/jats:p>\n                    <jats:sec>\n                      <jats:title>IMPORTANCE<\/jats:title>\n                      <jats:p>\n                        Epstein-Barr virus (EBV) causes several cancers, and the normal counterparts of major EBV-associated cancers have been identified in the germinal center model (GCM) of EBV persistence in humans. We searched for the normal\n                        <jats:italic toggle=\"yes\">in vivo<\/jats:italic>\n                        counterparts of immunoblastic B-cell lymphoma (IL) that occurs in immunosuppressed individuals. IL resembles\n                        <jats:italic toggle=\"yes\">in vitro<\/jats:italic>\n                        EBV-infected B cells driven by EBV to become indefinitely proliferating lymphoblastoid cell lines (LCLs). Here, we demonstrate that EBV-infected tonsillar marginal zone (MZ) B cells, which are GC-independent, are the\n                        <jats:italic toggle=\"yes\">in vivo<\/jats:italic>\n                        correlates of LCLs\/ILs and the plausible precursors of IL in humans. EBV-infected MZ B cells express the EBV growth program with high expression of the oncogenic LMP1 and the DNA-mutating enzyme AID and are proliferating extensively. AID expression, rapid proliferation, and LMP1 expression put these cells at high risk for cancer development. Clinical interventions that target LMP1-expressing MZ B cells should dramatically decrease the incidence of IL.\n                      <\/jats:p>\n                    <\/jats:sec>\n                  <\/jats:sec>","DOI":"10.1128\/jvi.01051-24","type":"journal-article","created":{"date-parts":[[2025,7,8]],"date-time":"2025-07-08T08:38:42Z","timestamp":1751963922000},"update-policy":"https:\/\/doi.org\/10.1128\/asmj-crossmark-policy-page","source":"Crossref","is-referenced-by-count":3,"title":["Epstein-Barr virus-infected tonsillar marginal zone B cells\n                    <i>in vivo<\/i>\n                    as a precursor for immunosuppression-related B-cell lymphoma"],"prefix":"10.1128","volume":"99","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-7522-8216","authenticated-orcid":true,"given":"Charles","family":"Torgbor","sequence":"first","affiliation":[{"id":[{"id":"https:\/\/ror.org\/05wvpxv85","id-type":"ROR","asserted-by":"publisher"}],"name":"Tufts University School of Medicine","place":["Boston, USA"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"David A.","family":"Thorley-Lawson","sequence":"additional","affiliation":[{"id":[{"id":"https:\/\/ror.org\/05wvpxv85","id-type":"ROR","asserted-by":"publisher"}],"name":"Tufts University School of Medicine","place":["Boston, USA"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-1113-2829","authenticated-orcid":true,"given":"Ann M.","family":"Moormann","sequence":"additional","affiliation":[{"id":[{"id":"https:\/\/ror.org\/0464eyp60","id-type":"ROR","asserted-by":"publisher"}],"name":"Department of Medicine, University of Massachusetts Medical School","place":["Worcester, USA"]}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"235","reference":[{"key":"e_1_3_5_2_2","doi-asserted-by":"publisher","DOI":"10.4084\/MJHID.2009.032"},{"key":"e_1_3_5_3_2","doi-asserted-by":"publisher","DOI":"10.1002\/hon.751"},{"key":"e_1_3_5_4_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.semcancer.2013.07.005"},{"key":"e_1_3_5_5_2","doi-asserted-by":"publisher","DOI":"10.1056\/NEJM199805143382003"},{"key":"e_1_3_5_6_2","first-page":"2468","article-title":"Heterogeneity among Epstein-Barr virus-seropositive donors in the generation of immunoblastic B-cell lymphomas in SCID mice receiving human peripheral blood leukocyte grafts","volume":"52","author":"Picchio GR","year":"1992","unstructured":"Picchio GR, Kobayashi R, Kirven M, Baird SM, Kipps TJ, Mosier DE. 1992. 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