Epstein-Barr virus (EBV) is a ubiquitous human herpesvirus linked to a number of 
B cell cancers and lymphoproliferative disorders. During latent infection, EBV 
expresses 25 viral pre-microRNAs (miRNAs) and induces the expression of specific 
host miRNAs, such as miR-155 and miR-21, which potentially play a role in viral 
oncogenesis. To date, only a limited number of EBV miRNA targets have been 
identified; thus, the role of EBV miRNAs in viral pathogenesis and/or 
lymphomagenesis is not well defined. Here, we used photoactivatable 
ribonucleoside-enhanced crosslinking and immunoprecipitation (PAR-CLIP) combined 
with deep sequencing and computational analysis to comprehensively examine the 
viral and cellular miRNA targetome in EBV strain B95-8-infected lymphoblastoid 
cell lines (LCLs). We identified 7,827 miRNA-interaction sites in 3,492 cellular 
3'UTRs. 531 of these sites contained seed matches to viral miRNAs. 24 
PAR-CLIP-identified miRNA:3'UTR interactions were confirmed by reporter assays. 
Our results reveal that EBV miRNAs predominantly target cellular transcripts 
during latent infection, thereby manipulating the host environment. Furthermore, 
targets of EBV miRNAs are involved in multiple cellular processes that are 
directly relevant to viral infection, including innate immunity, cell survival, 
and cell proliferation. Finally, we present evidence that myc-regulated host 
miRNAs from the miR-17/92 cluster can regulate latent viral gene expression. 
This comprehensive survey of the miRNA targetome in EBV-infected B cells 
represents a key step towards defining the functions of EBV-encoded miRNAs, and 
potentially, identifying novel therapeutic targets for EBV-associated 
malignancies.