Epstein-Barr virus lytic reactivation regulation and its pathogenic role in carcinogenesis

Abstract

Epstein-Barr virus (EBV) has been associated with several types of human cancers. In the host, EBV can establish two alternative modes of life cycle, known as latent or lytic and the switch from latency to the lytic cycle is known as EBV reactivation. Although EBV in cancer cells is found mostly in latency, a small number of lytically-infected cells promote carcinogenesis through the release of growth factors and oncogenic cytokines. This review focuses on the mechanisms by which EBV reactivation is controlled by cellular and viral factors, and discusses how EBV lytic infection contributes to human malignancies.

Keywords: Epstein-Barr virus; Rta; Zta; carcinogenesis; latency; reactivation.

Figure 1

Signaling pathways of BZLF1 promoter activation. EBV reactivation can be induced by BCR-mediated signaling pathways or cellular stress (e.g., DNA damage). PKC, MAPK (ERKs, JNKs, and p38), and PI3K pathways as well as ATM-dependent mechanisms appear to be involved. A network with crosstalk of four major signaling pathways leads to activation of several positive transcription factors, followed by transcription from Zp.

Figure 2

Epigenetic control of EBV lytic reactivation. a. During latency, EBV lytic promoters are silenced by host-driven methylation. The IE protein Zta preferentially binds to methylated ZREs (meZREs) in lytic promoters to initiate replication from this epigenetic repressed state. b. The IE promoters Zp and Rp are controlled by several repressive histone modifications during EBV latent infection. After nucleosomes are removed locally, activating histone marks are established and allow the access of transcription factors to induce expression of both IE genes.

Figure 3

Schematic indicating the role of cellular and EBV miRNAs in EBV latency and reactivation. Cellular miRNAs have distinct functions in EBV latency and lytic reactivation by directly targeting transcription factors on Zp or regulating the signaling pathway related to expression of Zta. Nevertheless, the EBV-encoded miRNAs inhibit the transition from latent to lytic viral replication, which occurs both through modulation of specific signaling pathways as well as through the restriction of its own gene expression. Notably, the EBV-encoded mi-BART20-5p can directly target the transcripts of the BZLF1 and BRLF1 genes.

Figure 4

The pathogenic role of EBV lytic infection in NPC carcinogenesis. After primary infection, EBV establishes latent infection in B cells. Upon reactivation, lytically-infected B cells travel through the nasopharynx tissue, followed by infection of the nasopharyngeal epithelial cells by cell-to-cell contact. Similar to the LMP1 oncoprotein, the presence of a limited number of lytically-infected epithelial cells induces genome instability and release of oncogenic cytokines, consequently promoting NPC carcinogenesis. Although NPC is sensitive to radiotherapy, extensive resistance to radiation often causes tumor metastasis or relapse after remission. IR -induced recurrent expression of lytic proteins is a potential factor that mediates the impact of EBV on NPC relapse. The fluctuation of EBV antibody titers reflects tumor progression of NPC.