Inhibitors of APE1 redox function effectively inhibit γ-herpesvirus replication in vitro and in vivo

APE1 is a multi-functional protein with a redox function in its N-terminal domain and an apurinic/apyrimidinic endonuclease activity in the C-terminal domain. APE1 redox function plays an important role in regulating cell proliferation and survival through activating specific transcriptional activators. APE1 redox function is also found to be associated with some cancer occurrence. In this study, we demonstrated that APE1 redox function is essential for Epstein-Barr virus (EBV) lytic replication as the silencing of APE1 expression or treatment with APE1 redox inhibitors C10 and E3330 can inhibit EBV lytic replication and virion production. Furthermore, C10 and E3330 also inhibit MHV-68 replication in vitro and in vivo. C10 and E3330 were able to significantly reduce the loss of pulmonary alveoli and thickening of alveolar septa in mice caused by MHV-68 infection. Altogether, (i) APE1 redox function is validated as a new antiviral target; (ii) APE1 redox inhibitors, especially C10, have potentials to be used for the treatment of γ-herpesvirus infection and associated diseases; (iii) MHV-68 is validated to be a surrogate for the study of the pathogenesis and therapy of EBV and KSHV infection in vivo.