Regulation of the latent-lytic switch in Epstein-Barr virus

Abstract

Epstein-Barr virus (EBV) infection contributes to the development of several different types of human malignancy, including Burkitt lymphoma, Hodgkin lymphoma, and nasopharyngeal carcinoma. As a herpesvirus, EBV can establish latent or lytic infection in cells. EBV-positive tumors are composed almost exclusively of cells with latent EBV infection. Strategies for inducing the lytic form of EBV infection in tumor cells are being investigated as a potential therapy for EBV-positive tumors. In this article, we review how cellular and viral proteins regulate the latent-lytic EBV switch in infected B cells and epithelial cells, and discuss how harnessing lytic viral reactivation might be used therapeutically.

Keywords: Ataxia-telangiectasia mutated (ATM); Genome methylation; Hypoxia; Lytic induction therapy; TGF-β.

Fig. 1

Schematics (not drawn to accurate scale) showing (A) the locations of the BZLF1 and BRLF1 genes within the context of the EBV genome, and (B and C) factors known to play roles in regulating transcription from the promoters of these genes, Zp and Rp, respectively. Cis-acting elements are indicated by gray rectangles, with their corresponding trans-acting factors shown directly above or below them. ZRE, Z-responsive element; SBE, Smads-responsive element; and HRE, hypoxia-responsive element.

Fig. 2

Some cellular signaling pathways that can lead to EBV reactivation. Shown here are highly simplified schematics indicating some of the key players involved in inducing transcriptional activation of Zp and/or Rp by (A) differentiation of B cells into plasma cells, (B) TGF-β1, (C) hypoxia, and (D) a variety of agents that induce DNA damage or reactive oxygen species (ROS). See text for details. P, phosphorylation.

Fig. 3

Schematic indicating role of EBV genome methylation in determining whether EBV reactivation is initially induced by Z or R protein in B cells versus telomerase-immortalized normal oral keratinocytes, respectively. Once either Z or R protein is synthesized in a cell type-dependent manner, it induces synthesis of the other immediate-early protein, with the two proteins then inducing the cascade of events that leads to production of infectious virus particles. See text for details.

Fig. 4

Strategy of lytic-induction therapy for treating patients with EBV-positive tumors using a combination of EBV lytic-inducing agents and ganciclovir. Lytic EBV reactivation in a portion of the tumor cells by one or more inducing agents leads to synthesis of the EBV-encoded thymidine and protein kinases (TK and PK, respectively). The PK then converts GCV to an active form by phosphorylation. Phosphorylated GCV inhibits both cellular and viral DNA replication, leading to cell death. It also spreads to nearby cells, killing these cells as well. Cells lacking phosphorylated GCV continue to replicate their DNA normally. See text for details.