Interferon regulatory factor 7 (IRF7) was originally identified in the context of Epstein–Barr virus (EBV) infection, and has since emerged as the crucial regulator of type I interferons (IFNs) against pathogenic infections, which activate IRF7 by triggering signaling cascades from pathogen recognition receptors (PRRs) that recognize pathogenic nucleic acids. Moreover, IRF7 is a multifunctional transcription factor, underscored by the fact that it is associated with EBV latency, in which IRF7 is induced as well as activated by the EBV principal oncoprotein latent membrane protein-1 (LMP1). Aberrant production of type I IFNs is associated with many types of diseases such as cancers and autoimmune disorders. Thus, tight regulation of IRF7 expression and activity is imperative in dictating appropriate type I IFN production for normal IFN-mediated physiological functions. Posttranslational modifications have important roles in regulation of IRF7 activity, exemplified by phosphorylation, which is indicative of its activation. Furthermore, mounting evidence has shed light on the importance of regulatory ubiquitination in activation of IRF7. Albeit these exciting findings have been made in the past decade since its discovery, many questions related to IRF7 remain to be addressed.

Despite the well-established tropism of the Epstein-Barr virus (EBV) for human B lymphocytes, the cell type within the oropharynx capable of allowing EBV replication has never been conclusively identified. Using in situ cytohybridization, we demonstrated EBV DNA in oropharyngeal epithelial cells from 10 of 12 patients with infectious mononucleosis. In duplicates of specimens found to contain cell-associated EBV DNA, we detected EBV RNA in two of four samples, using a biotin-labeled EBV DNA probe, thereby confirming the intracellular location of the viral genome. In 20 of 28 throat washings analyzed, cytohybridization results and assays for cell-free infectious virus were in agreement. In seven of the eight remaining specimens, cytohybridization identified intracellular EBV DNA in the absence of detectable extracellular virus. We conclude that the oropharyngeal epithelial cell may be the target cell type that is productively infected in infectious mononucleosis.

It has emerged recently that exosomes are potential carriers of pro-tumorigenic factors that participate in oncogenesis. However whether oncogenic transcription factors are transduced by exosomes is unknown. Hypoxia-inducible factor-1alpha (HIF-1α) transcriptionally regulates numerous key aspects of tumor development and progression by promoting a more aggressive tumor phenotype, characterized by increased proliferation and invasiveness coupled with neoangiogenesis. It has been shown that the principal oncoprotein of Epstein-Barr Virus (EBV), Latent Membrane Protein 1 (LMP1), drives oncogenic processes and tumor progression of the highly invasive EBV malignancy, nasopharyngeal carcinoma (NPC). We now demonstrate that endogenous HIF-1α is detectable in exosomes, and that LMP1 significantly increases levels of HIF-1α in exosomes. HIF-1 recovered from exosomes retains DNA-binding activity and is transcriptionally active in recipient cells after exosome uptake. We show also that treatment of EBV-negative cells with LMP1-exosomes increases migration and invasiveness of NP cell lines in functional assays, which correlates with the phenotype associated with Epithelial Mesenchymal Transition (EMT). In addition we provide evidence that HIF1α itself participates in exosome-mediated pro-metastatic effects in recipient cells, since exosome-mediated delivery of active and inactive forms of HIF-1α results in reciprocal changes in expression of E- and N-cadherins associated with EMT. Further, immunohistochemical analysis of NPC tumor tissues revealed direct correlation between protein levels of LMP1 and of the endosome/exosome marker tetraspanin, CD63, which suggests an increase in exosome formation in this EBV-positive malignancy. We hypothesize that exosome-mediated transfer of functional pro-metastatic factors by LMP1-positive NPC cells to surrounding tumor cells promotes cancer progression.

The Epstein-Barr virus (EBV)BamHI