EBV microRNA BART 18-5p targets MAP3K2 to facilitate persistence in vivo by inhibiting viral replication in B cells

EBV is an oncogenic human herpesvirus that has the ability to infect and transform B cells latently in vitro. However, the virus also establishes a lifetime, benign, persistent latent infection in resting memory B cells in vivo, where the virus is quiescent (i.e., expresses none of the known latent proteins). The virus encodes ∼40 micro-RNAs (miRNAs), most of which are transcribed from the BamH1 fragment A rightward transcript (BART) region of the virus. We have shown previously that a subset of these miRNAs is present at high copy numbers in latently infected memory B cells in vivo, suggesting a role in maintaining latency. Here, we describe the role of one of these miRNAs, BART 18-5p. We show that it targets the 3'UTR of the mRNA, encoding the important cellular signaling molecule MAP kinase kinase kinase 2 (MAP3K2), at exactly the same site as the oncogenic cellular miRNA mir-26a-5p. To our knowledge, this is the first report of a virus encoding a miRNA that suppresses a target in the MAP kinase signaling cascade, a central signal transduction pathway that governs a broad spectrum of biological processes. We further show that MAP3K2 is an intermediary in the signaling pathways that initiate lytic viral replication. Thus, 18-5p expression in latently infected B cells has the effect of blocking viral replication. We propose that the role of 18-5p is to maintain latency by reducing the risk of fortuitous reactivation of the virus in latently infected memory B cells.