Epstein Barr Virus
Epstein-Barr virus (EBV) is a human γ-herpesvirus that is able to establish a long-term, latent infection in human B cells for the life of the host. EBV infection is associated with a range of human cancers, including Burkitt’s lymphoma (BL) and Hodgkin’s disease, as well as several AIDS-associated cancers of which the most prevalent is diffuse large B-cell lymphoma (DLBCL). It has been proposed that EBV initially infects naïve B cells and then induces these to undergo a period of rapid proliferation leading eventually to differentiation into a pool of latently EBV-infected cells that resemble memory B cells. These two successive phases are referred to as EBV latency III and EBV latency I. During latency III, EBV expresses a set of nine proteins—the EBV nuclear antigen (EBNA) proteins EBNA-1, -2, -3A, -3B, -3C and -LP and the latent membrane proteins (LMPs) LMP-1, -2A and -2B—that are thought to mimic the ordered activation process that a naïve B cell would normally undergo after antigenic stimulation. Eventually, these cells cycle back into a differentiation state that resembles a memory B cell, at which point EBV protein expression becomes restricted to EBNA-1.Previously published models for EBV latency proposed that the reprogramming of B cells after EBV infection largely reflected the action of viral proteins. These were thought to modify the pattern of cellular gene expression either directly, by acting as transcription factors, or indirectly, by mimicking the signals normally generated at the cell surface during antigenic stimulation. However, recent data have also revealed that EBV encodes two microRNA cluster that encode no fewer than 25 distinct microRNAs (miRNAs) that have the potential to also play a critical role in the establishment and/or maintenance of EBV latency. Moreover, it is now clear that EBV infection greatly perturbs the pattern of cellular miRNA expression in infected B cells. In particular, EBV infection of resting primary B cells has been shown to strongly activate the expression of miR-155 and a small number of other cellular miRNAs. Recently, we demonstrated that miR-155 is, in fact, essential for the establishment and maintenance of EBV-transformed B cells in culture and we have also demonstrated that the virally encoded miR-BHRF1 cluster of miRNAs play a key in the transformation of primary B cells by EBV in culture.
In addition to B cells, EBV also infects epithelial cells, where it can also establish latent infections that lead to cell transformation giving rise , for example , to high levels of nasopharyngeal carcinoma (NPC) in east Asia. In NPCs, EBV expresses high levels of microRNAs from the miR-BART cluster which we have recently shown down-regulate pro-apoptotic genes and can protect these tumor cells from chemotherapeutic agents.. Currently, we remain focused on identifying and validating mRNA targets downregulated by miR-155 and the EBV miRNAs in infected cells. Work on EBV at Duke University Medical Center is performed as a collaboration between the Cullen laboratory and the laboratory of Dr. Micah Luftig, which is also in the Department of Molecular Genetics & Microbiology.