Dis Model Mech. 2014 Feb 20. [Epub ahead of print] A yeast-based assay identifies drugs that interfere with Epstein-Barr virus immune evasion. Voisset C1, Daskalogianni C, Contesse MA, Mazars A, Arbach H, Le Cann M, Soubigou F, Apcher S, Fåhraeus R, Blondel M. Author information Abstract AbstractEpstein-Barr virus (EBV) is tightly associated to certain human cancers but there is of today no specific treatment against EBV-related diseases. The EBV-encoded EBNA1 protein is essential to maintain viral episomes and for viral persistence. EBNA1 is expressed in all EBV infected cells and is highly antigenic. All infected individuals, including cancer patients, have CD8+ T cells directed towards EBNA1 epitopes, yet the immune system fails to detect and destroy cells harboring the virus. EBV's immune evasion depends on the capacity of the Gly-Ala repeat (GAr) domain of EBNA1 to inhibit the translation of its own mRNA in cis, thereby limiting the production of EBNA1-derived antigenic peptides presented by the Major Histocompatibility Complex (MHC) class I pathway. Here we establish a yeast-based assay for monitoring GAr-dependent inhibition of translation. Using this assay we identify doxorubicin (DXR) as a compound that specifically interferes with the GAr effect on translation in yeast. DXR targets the topoisomerase II/DNA complexes and thereby causes genomic damage. We show, however, that the genotoxic effect of DXR and various analogues thereof is uncoupled from the effect on GAr-mediated translation control. This is further supported by the observation that etoposide and teniposide, representing another class of topoisomerase II/DNA targeting drugs, have no effect on GAr-mediated translation control. DXR and active analogues stimulate in a GAr-dependent manner EBNA1 expression in mammalian cells and overcome GAr-dependent restriction of MHC class I antigen presentation. These results validate our approach as an effective high-throughput screening assay to identify drugs that interfere with EBV immune evasion and, thus, constitute candidates for treating EBV-related diseases, in particular EBV-associated cancers.