Epstein-Barr Virus: How Its Lytic Phase Contributes to Oncogenesis

Abstract

Epstein-Barr Virus (EBV) contributes to the development of lymphoid and epithelial malignancies. While EBV's latent phase is more commonly associated with EBV-associated malignancies, there is increasing evidence that EBV's lytic phase plays a role in EBV-mediated oncogenesis. The lytic phase contributes to oncogenesis primarily in two ways: (1) the production of infectious particles to infect more cells, and (2) the regulation of cellular oncogenic pathways, both cell autonomously and non-cell autonomously. The production of infectious particles requires the completion of the lytic phase. However, the regulation of cellular oncogenic pathways can be mediated by an incomplete (abortive) lytic phase, in which early lytic gene products contribute substantially, whereas late lytic products are largely dispensable. In this review, we discuss the evidence of EBV's lytic phase contributing to oncogenesis and the role it plays in tumor formation and progression, as well as summarize known mechanisms by which EBV lytic products regulate oncogenic pathways. Understanding the contribution of EBV's lytic phase to oncogenesis will help design ways to target it to treat EBV-associated malignancies.

Keywords: EBV; immune evasion; lytic phase; lytic reactivation; oncogenesis; tumor survival.

Figure 1

EBV’s lytic phase contributes to oncogenesis in both B cells and epithelial cells. In this figure, B cell lymphomagenesis is used to represent these contributions. Following primary infection and transformation, EBV is maintained latently in infected cells. On rare occasions, some cells undergo lytic reactivation, either completely or incompletely. Cells that undergo the complete lytic reactivation express both early and late lytic genes and produce new viral particles that can infect more cells. These newly infected cells are transformed and may subsequently evolve into tumor cells. Cells that complete the lytic phase eventually die, such that they do not contribute as proliferating tumor cells. However, they can contribute to oncogenesis via non-cell-autonomous mechanisms mediated by early lytic gene products. These contributions include angiogenesis, pro-tumorigenic cytokine production, and, in the case of NPCs, extracellular matrix modifications. Some cells that enter the lytic phase do not complete it, undergoing incomplete (abortive) lytic reactivation. These cells express early lytic genes but not late lytic genes, and thus do not produce new viral particles. These cells may continue to live, and contribute to oncogenesis cell autonomously by becoming tumor cells with increased proliferation, immune evasion, and genomic instability, as well as decreased apoptosis. Having expressed early lytic genes, abortive lytic cells may also contribute to oncogenesis non-cell autonomously. * Expression of latent, early lytic, or late lytic genes are indicated in blue (expressed) and red (not expressed). ** Extracellular matrix modifications are primarily studied in NPCs.