Mühe, JanineWang, Fred2018-02-262017Mühe, Janine, and Fred Wang. 2017. “Species-specific functions of Epstein-Barr virus nuclear antigen 2 (EBNA2) reveal dual roles for initiation and maintenance of B cell immortalization.” PLoS Pathogens 13 (12): e1006772. doi:10.1371/journal.ppat.1006772. http://dx.doi.org/10.1371/journal.ppat.1006772.http://nrs.harvard.edu/urn-3:HUL.InstRepos:34868802Epstein-Barr virus (EBV) and related lymphocryptoviruses (LCV) from non-human primates infect B cells, transform their growth to facilitate life-long viral persistence in the host, and contribute to B cell oncogenesis. Co-evolution of LCV with their primate hosts has led to species-specificity so that LCVs preferentially immortalize B cells from their natural host in vitro. We investigated whether the master regulator of transcription, EBV nuclear antigen 2 (EBNA2), is involved in LCV species-specificity. Using recombinant EBVs, we show that EBNA2 orthologues of LCV isolated from chimpanzees, baboons, cynomolgus or rhesus macaques cannot replace EBV EBNA2 for the immortalization of human B cells. Thus, LCV species-specificity is functionally linked to viral proteins expressed during latent, growth-transforming infection. In addition, we identified three independent domains within EBNA2 that act through species-specific mechanisms. Importantly, the EBNA2 orthologues and species-specific EBNA2 domains separate unique roles for EBNA2 in the initiation of B cell immortalization from those responsible for maintaining the immortalized state. Investigating LCV species-specificity provides a novel approach to identify critical steps underlying EBV-induced B cell growth transformation, persistent infection, and oncogenesis.en-USBiology and Life SciencesCell BiologyCellular TypesAnimal CellsImmune CellsAntibody-Producing CellsB CellsImmunologyMedicine and Health SciencesBlood CellsWhite Blood CellsCell PhysiologyCell ImmortalizationBiology and life sciencesOrganismsVirusesDNA virusesHerpesvirusesEpstein-Barr virusMicrobiologyMedical microbiologyMicrobial pathogensViral pathogensMedicine and health sciencesPathology and laboratory medicinePathogensGeneticsGene ExpressionTransactivationBiochemistryHormonesEstrogensMolecular BiologyMolecular Biology TechniquesMolecular Probe TechniquesImmunoblottingMolecular biologyMolecular biology techniquesDNA constructionPlasmid ConstructionCell ProcessesCell GrowthJournal Article2018-02-2610.1371/journal.ppat.1006772