Latent Epstein-Barr virus (EBV) infection is causally linked to several human cancers.
EBV expresses viral oncogenes that promote cell growth and inhibit the apoptotic response to
uncontrolled proliferation. The EBV oncoprotein LMP1 constitutively activates NFkB and is critical
for survival of EBV-immortalized B cells. However, during early infection EBV induces rapid B cell
proliferation with low levels of LMP1 and little apoptosis. Therefore, we sought to define the
mechanism of survival in the absence of LMP1/NFkB early after infection. We used BH3 profiling to
query mitochondrial regulation of apoptosis and defined a transition from uninfected B cells (BCL2)
to early-infected (MCL-1/BCL-2) and immortalized cells (BFL-1). This dynamic change in B cell
survival mechanisms is unique to virus-infected cells and relies on regulation of MCL-1
mitochondrial localization and BFL-1 transcription by the viral EBNA3A protein. This study defines a
new role for EBNA3A in the suppression of apoptosis with implications for EBV lymphomagenesis.