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How lymphoblastoid cell lines (LCLs) evolve from the infected lymphocytes is uncertain. We conducted a systematic time-resolved longitudinal study of cellular functions and transcriptional profiles of newly infected na\u00efve primary B lymphocytes. EBV reprograms the cells comprehensively and globally. Rapid and extensive transcriptional changes occur within 24 h and precede any metabolic and phenotypic changes. Within 72 h, the virus activates the cells, changes their phenotypes with respect to cell size, RNA, and protein content, and induces metabolic pathways to cope with the increased demand for energy, supporting an efficient cell cycle entry on day 3 postinfection. The transcriptional program that EBV initiates consists of 3 waves of clearly discernable clusters of cellular genes that peak on day 2, 3, or 4 and regulate RNA synthesis, metabolic pathways, and cell division, respectively. Upon onset of cell doublings on day 4, the cellular transcriptome appears to be completely reprogrammed to support the proliferating cells, but 3 additional clusters of EBV-regulated genes fine-tune cell signaling, migration, and immune response pathways, eventually. Our study reveals that more than 11,000 genes are regulated upon EBV infection as na\u00efve B cells exit quiescence to enter a germinal center-like differentiation program, which culminates in immortalized, proliferating cells that partially resemble plasmablasts and early plasma cells.<\/jats:p>","DOI":"10.1073\/pnas.1901314116","type":"journal-article","created":{"date-parts":[[2019,7,24]],"date-time":"2019-07-24T19:15:52Z","timestamp":1563995752000},"page":"16046-16055","update-policy":"https:\/\/doi.org\/10.1073\/pnas.cm10313","source":"Crossref","is-referenced-by-count":208,"title":["Epstein\u2013Barr virus reprograms human B lymphocytes immediately in the prelatent phase of infection"],"prefix":"10.1073","volume":"116","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-2678-4558","authenticated-orcid":false,"given":"Paulina","family":"Mrozek-Gorska","sequence":"first","affiliation":[{"name":"Research Unit Gene Vectors, Helmholtz Zentrum M\u00fcnchen, German Research Center for Environmental Health and German Center for Infection Research, D-81377 Munich, Germany;"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-6126-514X","authenticated-orcid":false,"given":"Alexander","family":"Buschle","sequence":"additional","affiliation":[{"name":"Research Unit Gene Vectors, Helmholtz Zentrum M\u00fcnchen, German Research Center for Environmental Health and German Center for Infection Research, D-81377 Munich, Germany;"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Dagmar","family":"Pich","sequence":"additional","affiliation":[{"name":"Research Unit Gene Vectors, Helmholtz Zentrum M\u00fcnchen, German Research Center for Environmental Health and German Center for Infection Research, D-81377 Munich, Germany;"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Thomas","family":"Schwarzmayr","sequence":"additional","affiliation":[{"name":"Institute of Human Genetics, Helmholtz Zentrum M\u00fcnchen, German Research Center for Environmental Health, D-85764 Neuherberg, Germany;"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ron","family":"Fechtner","sequence":"additional","affiliation":[{"name":"Institute of Epigenetics and Stem Cells, Helmholtz Zentrum M\u00fcnchen, German Research Center for Environmental Health, D-81377 Munich, Germany;"},{"name":"Institute of Computational Biology, Helmholtz Zentrum M\u00fcnchen, German Research Center for Environmental Health, D-85764 Neuherberg, Germany;"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Antonio","family":"Scialdone","sequence":"additional","affiliation":[{"name":"Institute of Epigenetics and Stem Cells, Helmholtz Zentrum M\u00fcnchen, German Research Center for Environmental Health, D-81377 Munich, Germany;"},{"name":"Institute of Computational Biology, Helmholtz Zentrum M\u00fcnchen, German Research Center for Environmental Health, D-85764 Neuherberg, Germany;"},{"name":"Institute of Functional Epigenetics, Helmholtz Zentrum M\u00fcnchen, German Research Center for Environmental Health, D-85764 Neuherberg, Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-4659-0427","authenticated-orcid":false,"given":"Wolfgang","family":"Hammerschmidt","sequence":"additional","affiliation":[{"name":"Research Unit Gene Vectors, Helmholtz Zentrum M\u00fcnchen, German Research Center for Environmental Health and German Center for Infection Research, D-81377 Munich, Germany;"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"341","published-online":{"date-parts":[[2019,7,24]]},"reference":[{"key":"e_1_3_4_1_2","doi-asserted-by":"crossref","first-page":"702","DOI":"10.1016\/S0140-6736(64)91524-7","article-title":"Virus particles in cultured lymphoblasts from Burkitt\u2019s lymphoma","volume":"1","author":"Epstein M. 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