Epstein-Barr Virus Modulates Host Cell MicroRNA-194 to Promote IL-10 Production and B Lymphoma Cell Survival

Epstein-Barr virus (EBV) is a -herpesvirus that is linked to the development of posttransplant lymphoproliferative disorder (PTLD) in solid organ recipients. We previously demonstrated that EBV+ B cell lymphoma cell lines isolated from patients with PTLD produce human IL-10 as an autocrine growth factor. However, little is known regarding IL-10 regulation in B cells. Here we show that EBV infection markedly alters the expression of host B cell microRNA, a class of small noncoding RNA that is an important regulator of transcriptional and posttranscriptional gene expression. Gene arrays reveal unique microRNA profiles in EBV+ B cell lymphoma lines from patients with PTLD, compared to normal B cells or in vitro generated EBV+ lymphoblastoid cell lines. We show that microRNA-194 expression is uniquely suppressed in EBV+ B cell lines from PTLD patients and that the 3'untranslated region of IL-10 is targeted by microRNA-194. Overexpression of microRNA-194 attenuates IL-10 production and increases apoptosis of EBV+ B cell lymphoma lines. Together, these data indicate that EBV co-opts the host B cell microRNA network and specifically suppresses microRNA-194 to override control of IL-10 expression. Thus, modulation of microRNA-194 may constitute a novel approach to inhibiting proliferation of EBV+ B cell lymphomas in PTLD.