{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"institution":[{"name":"bioRxiv"}],"indexed":{"date-parts":[[2026,1,18]],"date-time":"2026-01-18T18:51:08Z","timestamp":1768762268907,"version":"3.49.0"},"posted":{"date-parts":[[2025,1,18]]},"group-title":"Microbiology","reference-count":54,"publisher":"openRxiv","license":[{"start":{"date-parts":[[2025,1,18]],"date-time":"2025-01-18T00:00:00Z","timestamp":1737158400000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/creativecommons.org\/licenses\/by-nd\/4.0\/"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":[],"accepted":{"date-parts":[[2025,1,18]]},"abstract":"<jats:title>Abstract<\/jats:title>\n                <jats:p>\n                  X-linked Lymphoproliferative Syndromes (XLP), which arise from mutations in the\n                  <jats:italic>SH2D1A<\/jats:italic>\n                  or\n                  <jats:italic>XIAP<\/jats:italic>\n                  genes, are characterized by the inability to control Epstein-Barr Virus (EBV) infection. While primary EBV infection triggers severe diseases in each, lymphomas occur at high rates with XLP-1 but not with XLP-2. Why XLP-2 patients are apparently protected from EBV-driven lymphomagenesis, in contrast to all other described congenital conditions that result in heightened susceptibility to EBV, remains a key open question. To gain insights, we cross-compared newly EBV infected versus immune stimulated B-cells from XLP-2 patients or upon XIAP CRISPR knockout, relative to healthy controls. XIAP perturbation impeded outgrowth of newly EBV-infected primary human B-cells, though had no impact on proliferation of B-cells stimulated by CD40 ligand and interleukin-21 or upon established EBV-immortalized lymphoblastoid cell lines (LCLs). B-cells from XLP-2 patients or in which XIAP was depleted by CRISPR editing exhibited a markedly lower EBV transformation efficiency than healthy control B-cells. Mechanistically, nascent EBV infection activated p53-mediated apoptosis signaling, whose effects on transforming B-cell death were counteracted by XIAP. In the absence of XIAP, EBV infection triggered high rates of apoptosis, not seen with CD40L\/IL-21 stimulation. Moreover, inflammatory cytokines are present at high levels in XLP-2 patient serum with fulminant EBV infection, which heightened apoptosis induction in newly EBV-infected cells. These findings highlight the crucial role of XIAP in supporting early stages of EBV-driven B-cell immortalization and provide insights into the absence of EBV+ lymphoma in XLP-2 patients.\n                <\/jats:p>\n                <jats:sec>\n                  <jats:title>Key points<\/jats:title>\n                  <jats:list list-type=\"order\">\n                    <jats:list-item>\n                      <jats:p>XIAP loss-of-function markedly impairs EBV+ B-cells outgrowth over the first week post-infection, particularly in the presence of IFN-\u03b3.<\/jats:p>\n                    <\/jats:list-item>\n                    <jats:list-item>\n                      <jats:p>XIAP mutation impedes EBV-driven B-cell transformation by potentiating p53-driven caspase activation and apoptosis.<\/jats:p>\n                    <\/jats:list-item>\n                  <\/jats:list>\n                <\/jats:sec>","DOI":"10.1101\/2025.01.17.633616","type":"posted-content","created":{"date-parts":[[2025,1,18]],"date-time":"2025-01-18T06:50:12Z","timestamp":1737183012000},"source":"Crossref","is-referenced-by-count":0,"title":["Insights into the Absence of Lymphoma Despite Fulminant Epstein-Barr Virus Infection in Patients with XIAP Deficiency"],"prefix":"10.64898","author":[{"given":"Yizhe","family":"Sun","sequence":"first","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Janet","family":"Chou","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Kevin","family":"Dong","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Steven P.","family":"Gygi","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Benjamin E.","family":"Gewurz","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"54368","reference":[{"key":"2025012100450839000_2025.01.17.633616v1.1","doi-asserted-by":"publisher","DOI":"10.1146\/annurev-pathmechdis-012418-013023"},{"key":"2025012100450839000_2025.01.17.633616v1.2","doi-asserted-by":"publisher","DOI":"10.1038\/s41579-019-0249-7"},{"key":"2025012100450839000_2025.01.17.633616v1.3","unstructured":"Cohen JI , Mocarski Es Fau - Raab-Traub N , Raab-Traub N Fau - Corey L , Corey L Fau - Nabel GJ , Nabel GJ . The need and challenges for development of an Epstein-Barr virus vaccine. (1873-2518 (Electronic))."},{"key":"2025012100450839000_2025.01.17.633616v1.4","doi-asserted-by":"publisher","DOI":"10.1182\/blood-2009-07-143545"},{"key":"2025012100450839000_2025.01.17.633616v1.5","doi-asserted-by":"publisher","DOI":"10.1182\/blood.2019000928"},{"key":"2025012100450839000_2025.01.17.633616v1.6","doi-asserted-by":"crossref","unstructured":"Cohen JI . Primary Immunodeficiencies Associated with EBV Disease. In: M\u00fcnz C , ed. Epstein Barr Virus Volume 1: One Herpes Virus: Many Diseases. Cham: Springer International Publishing; 2015:241\u2013265.","DOI":"10.1007\/978-3-319-22822-8_10"},{"key":"2025012100450839000_2025.01.17.633616v1.7","unstructured":"Rickinson AB , Long HM , Palendira U , M\u00fcnz C , Hislop AD . Cellular immune controls over Epstein-Barr virus infection: new lessons from the clinic and the laboratory. 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