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Latency and lytic replication in Epstein–Barr virus-associated oncogenesis

Nature Reviews Microbiology volume 17, pages 691–700 (2019)Cite this article

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Abstract

Epstein–Barr virus (EBV) was the first tumour virus identified in humans. The virus is primarily associated with lymphomas and epithelial cell cancers. These tumours express latent EBV antigens and the oncogenic potential of individual latent EBV proteins has been extensively explored. Nevertheless, it was presumed that the pro-proliferative and anti-apoptotic functions of these oncogenes allow the virus to persist in humans; however, recent evidence suggests that cellular transformation is not required for virus maintenance. Vice versa, lytic EBV replication was assumed to destroy latently infected cells and thereby inhibit tumorigenesis, but at least the initiation of the lytic cycle has now been shown to support EBV-driven malignancies. In addition to these changes in the roles of latent and lytic EBV proteins during tumorigenesis, the function of non-coding RNAs has become clearer, suggesting that they might mainly mediate immune escape rather than cellular transformation. In this Review, these recent findings will be discussed with respect to the role of EBV-encoded oncogenes in viral persistence and the contributions of lytic replication as well as non-coding RNAs in virus-driven tumour formation. Accordingly, early lytic EBV antigens and attenuated viruses without oncogenes and microRNAs could be harnessed for immunotherapies and vaccination.

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Fig. 1: Models of latent Epstein–Barr virus infection to reach viral persistence.
Fig. 2: Persistence without transformation.
Fig. 3: Oncogenesis with lytic replication.
Fig. 4: Potential functions of lytic Epstein–Barr virus antigens and non-coding RNAs during Epstein–Barr virus-driven tumour formation.
Fig. 5: Lytic replication in clinical manifestations of Epstein–Barr virus infection.
Fig. 6: Non-coding RNAs in the Epstein–Barr virus genome.

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Acknowledgements

Research in C.M.’s laboratory is supported by Cancer Research Switzerland (KFS-4091-02-2017), KFSP-PrecisionMS of the University of Zürich, the Vontobel Foundation, the Baugarten Foundation, the Sobek Foundation, the Swiss Vaccine Research Institute, the Swiss Multiple Sclerosis Society, Roche, ReiThera and the Swiss National Science Foundation (310030B_182827 and CRSII5_180323).

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  1. Viral Immunobiology, Institute of Experimental Immunology, University of Zürich, Zürich, Switzerland

    Christian Münz

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Glossary

Burkitt’s lymphoma

The B cell tumour in which Epstein–Barr virus was discovered and that expresses EBNA1 as the only viral gene in the context of MYC translocations into the immunoglobulin locus.

Infectious mononucleosis

Immunopathological primary Epstein–Barr virus infection with massive CD8+ T cell lymphocytosis.

Latency

Virus persistence without virion production.

Germinal centre

The location of activated naive B cell differentiation with B cell receptor affinity maturation due to somatic hypermutation, in which centroblasts and centrocytes (activated and resting germinal centre B cells) need to receive signals via their B cell receptor engaging antigen on follicular dendritic cells (signal 1) and T cell help via CD40 (signal 2), in order to survive.

Abortive lytic replication

Early lytic viral gene expression without virion production.

Epstein–Barr nuclear antigen

An Epstein–Barr virus protein that is expressed during latent infection with oncogenic function.

Latent membrane proteins

An Epstein–Barr virus-encoded latent membrane protein that mimics signals that B cells have to receive in germinal centres for their survival and that contribute to viral oncogenesis.

BZLF1

An immediate early lytic transcription factor that initiates lytic Epstein–Barr virus replication from fully methylated viral DNA.

HIS mice

In the context of this review, immunodeficient mice with reconstituted human immune system compartments after transfer of human CD34+ haematopoietic progenitor cells or human cord blood mononuclear cells.

Superenhancers

Often distal genetic elements that strongly increase gene promoter activity.

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Münz, C. Latency and lytic replication in Epstein–Barr virus-associated oncogenesis. Nat Rev Microbiol 17, 691–700 (2019). https://doi.org/10.1038/s41579-019-0249-7

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