| Epstein-Barr virus (EBV) is an oncogenic herpesvirus associated with several B cell malignancies. Previous studies suggest that latent EBV infection contributes to lymphomagenesis by protecting B cell hosts from apoptosis. However, the relationship between EBV infection and sensitivity to death receptor (DR)-induced apoptosis is poorly understood. In this study, we provide the first evidence demonstrating EBV can protect a latently infected B cell lymphoma from apoptosis triggered through DRs. We showed that unlike uninfected control cells, BJAB lymphoma cells latently infected with the B95.8 strain of EBV (BJAB_B95) are completely resistant to apoptosis triggered through Fas or the TRAIL receptors DR4 and DR5. Caspase 8 activation was impaired and cFLIP recruitment was enriched in death inducing signaling complexes (DISCS) formed in EBV-infected BJAB cells relative to parent BJAB cells. Furthermore, the expression of the EBV latent membrane protein 1 (LMP1) alone could reduce caspase activation and confer partial resistance to death receptor apoptosis in BJAB cells. This protective effect was dependent on LMP1-induced NF-kappaB activation, which in turn upregulated cFLIP expression in LMP1+ BJAB cells. Finally, we showed that inhibition of NF-kappaB blocked cFLIP upregulation, reversed LMP1-mediated protection from DR apoptosis and sensitized BJAB_B95 cells to DR apoptosis as well. Thus, latent EBV can block DR apoptosis in host B cells, in part through the anti-apoptosic function of LMP1. Understanding the mechanisms by which latent EBV infection contributes to apoptosis resistance will hopefully improve our understanding and treatment of various EBV-associated neoplasms. |
