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.
Highlights
Epstein–Barr Virus (EBV)-positive malignancies have been associated with the latent phase of EBV’s life cycle; a non-productive phase in which no progeny virus is formed
What is meant by the term “EBV’s lytic phase”? To orient the reader, here we introduce the terminology that has developed with the study of EBV
Careful studies of viral gene expression during infection of primary B cells have led to the realization that multiple immediate early and early lytic genes of EBV are expressed during the first few days following infection, while others are introduced as proteins from the tegument of the viral particles
Summary
EBV-positive malignancies have been associated with the latent phase of EBV’s life cycle; a non-productive phase in which no progeny virus is formed. One naturally occurring variant within the BZLF1 promoter, termed Zp-V3, which can be bound by the NFAT transcription factor, increases an infected B cell’s responsiveness to entry into the lytic phase by treatment with anti-Ig antibodies, but does not affect the efficiency of transformation of primary B cells [29] This variant is found in approximately 50% of Burkitt Lymphomas (ibid.) and has no apparent effect on tumor formation in immunocompromised mice following reconstitution with human cord blood cells [30]. It does seem likely that variants of EBV that support their lytic phase more efficiently than do others would be more likely to yield higher viral loads in people and have an increased risk of being oncogenic This likelihood is supported by the observations that isolates with the Zp-V3 variant of the BZLF1 promoter occur twice as frequently in Burkitt Lymphomas and nasopharyngeal carcinomas as in non-malignant EBV-infected cells from people in the same regions of the world in which these cancers are found [29]
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