Epstein-Barr virus reactivation and DNA damage response

Abstract

The latent form of Epstein-Barr virus (EBV) is associated with many malignancies, including nasopharyngeal carcinoma, which makes EBV itself an attractive target of therapy. The reactivation of EBV toward lytic gene expression cascade will lead to expression of proteins involved in viral genome replication and formation of new virions, which will induce a strong immune response. The kinases expressed exclusively during the lytic cycle will also sensitize the tumor cells to antiviral treatment. This concept has recently been incorporated into a combination therapy, referred to as cytolytic virus activation therapy, in which a combination of gemcitabine (a chemoagent), valproic acid (a histone deacetylase inhibitor) and subsequent addition of ganciclovir (an antiviral agent), has been used in clinical studies with promising results. The molecular mechanisms by which these compounds co-operate, in order to trigger DNA damage response with subsequent lytic induction and tumor cytotoxicity, is discussed in this review. These agents are shown to work in multiple ways together. However, other EBV-associated malignancies might benefit form different set of compounds and this needs to be investigated. Further studies are required to analyze the effect of different combinations, in order to create potential stronger responses. These informations will be highly beneficial to treat other EBV-associated malignancies by use of EBV as the main target in a combination therapy.