Species-specific functions of Epstein-Barr virus nuclear antigen 2 (EBNA2) reveal dual roles for initiation and maintenance of B cell immortalization

Epstein-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 (rhlcv) 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. © 2017 mühe,wang.