Playing both sides – Epstein-Barr Virus accumulates select cellular transcripts to counter virus-mediated host shut-off in lytic cells

Epstein-Barr virus (EBV), an oncogenic virus, actively remodels the intracellular environment during its lytic (replicative/productive) phase to facilitate genome replication, virion packaging, and egress while attempting to evade immune responses. A key aspect of this remodeling is the downregulation of host gene expression, a phenomenon known as host shutoff. This process is prominently mediated by the EBV-encoded nuclease BGLF5 , but BGLF5 -independent mechanisms also contribute – most notably, the viral lytic switch protein ZEBRA, which can suppress host protein synthesis. Despite this broad suppression, the expression of certain host genes essential for lytic progression must be preserved or even enhanced. To investigate how such genes evade host shutoff, we analyzed the expression of a set of cellular transcripts in Burkitt lymphoma cells, sorted 24 hours after exposure to lytic triggers, into lytic and refractory (non-lytic) populations. We identified a subset of host transcripts consistently upregulated in lytic cells across Burkitt lymphoma lines reactivated by functionally distinct lytic stimuli, indicating that such upregulation is independent of pleiotropic lytic cycle inducing stimuli. Importantly, we found that while ZEBRA suppresses protein expression of some of these host (and select viral) genes, it also transcriptionally upregulates two related host genes, ELAVL4 and PABPC4L . Both encode RNA-binding proteins, and we found that they differentially modulate viral transcript abundance – enhancing some while repressing others – ultimately supporting the transcriptional demands, efficient genome replication and virion release during the EBV lytic cycle. These findings highlight the virus’s finely tuned regulation of both host and viral gene expression to ensure successful completion of the lytic cycle. Specifically, they suggest that EBV selectively upregulates critical host genes to counteract/escape host shutoff and promote virus propagation.