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

Epstein–Barr virus (EBV) is a γ‐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.