Epstein-Barr virus RNA confers resistance to interferon-alpha-induced apoptosis in Burkitt's lymphoma

Open Access
Publisher Website
Google Scholar
Abstract
We investigated whether Epstein–Barr virus (EBV) infection could counteract the antitumor effect of interferon (IFN)‐α. EBV‐negative subclones isolated from EBV‐positive Burkitt's lymphoma (BL) cell lines Akata, Daudi and Mutu were found to fall into apoptosis after IFN‐α treatment. On the other hand, EBV‐positive counterparts exhibited striking resistance against IFN‐α‐induced apoptosis. Transfection of an individual EBV latent gene into EBV‐negative BL cells revealed that EBV‐encoded poly(A)− RNAs (EBERs) were responsible for IFN resistance. EBERs bound double‐stranded (ds) RNA‐activated protein kinase (PKR), a key mediator of the antiviral effect of IFN‐α, and inhibited its phosphorylation. Transfection of dominant‐negative PKR, which was catalytically inactive and could block phosphorylation of endogenous PKR, made EBV‐negative BL cells resistant to IFN‐α‐induced apoptosis. Furthermore, EBERs did not bind mutant PKR, which was catalytically active but lacked dsRNA‐binding activity, nor did they inhibit its phosphorylation. These results indicate that EBERs confer resistance to IFN‐α‐induced apoptosis via binding to PKR and inhibition of its phosphorylation. This is the first report that the virus counteracts IFN‐induced apoptosis in virus‐associated tumors.