Epstein Barr virus (EBV) infects the majority of the human population and then usually persists asymptomatically within its host for life. The EBV oncoproteins nuclear antigen 3A (EBNA3A) and 3C (EBNA3C) are required for B cell transformation in vitro and have been found to be expressed in EBV-associated immunoblastic lymphomas in vivo. The authors were interested in the necessity of EBNA3A and EBNA3C for persistent EBV infection in vivo and therefore infected NOD-scid γcnull mice with reconstituted human immune system components (huNSG mice) with recombinant EBV mutants lacking EBNA3A or EBNA3C expression. These EBV mutants were found to establish latent infection in secondary lymphoid organs of infected huNSG mice for at least 3 months but did not lead to tumour formation. Low level viral persistence in the absence of EBNA3A or EBNA3C was primarily supported by proliferation, with the expression of early latent EBV gene products transitioning into absent viral protein expression without elevated lytic replication. The authors found that in vitro, EBNA3A- and EBNA3C-deficient EBV-infected B cells could be rescued from apoptosis by CD40 stimulation, which mimicks T cell help in secondary lymphoid tissues. Therefore, even in the absence of the oncogenes EBNA3A and 3C, EBV can still establish a latent gene expression pattern that is reminiscent of EBV persistence.
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