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Review
. 2023 Jan 30;15(3):855.
doi: 10.3390/cancers15030855.

EBV dUTPase: A Novel Modulator of Inflammation and the Tumor Microenvironment in EBV-Associated Malignancies

Marshall V Williams  1   2 , Irene Mena-Palomo  2 , Brandon Cox  2 , Maria Eugenia Ariza  1   2
Affiliations
Review

EBV dUTPase: A Novel Modulator of Inflammation and the Tumor Microenvironment in EBV-Associated Malignancies

Marshall V Williams et al. Cancers (Basel). .

Abstract

There is increasing evidence that put into question the classical dogma that the Epstein-Barr virus (EBV) exists in cells as either a lytic virus in which new progeny is produced or in a latent state in which no progeny is produced. Notably, a third state has now been described, known as the abortive-lytic phase, which is characterized by the expression of some immediate early (IE) and early (E) genes, but no new virus progeny is produced. While the function of these IE and E gene products is not well understood, several recent studies support the concept they may contribute to tumor promotion by altering the tumor microenvironment (TME). The mechanisms by which these viral gene products may contribute to tumorigenesis remain unclear; however, it has been proposed that some of them promote cellular growth, immune evasion, and/or inhibit apoptosis. One of these EBV early gene products is the deoxyuridine triphosphate nucleotidohydrolase (dUTPase) encoded by BLLF3, which not only contributes to the establishment of latency through the production of activin A and IL-21, but it may also alter the TME, thus promoting oncogenesis.

Keywords: Epstein–Barr virus; deoxyuridine triphosphate nucleotidohydrolase (dUTPase); germinal center (GC) reaction; herpesviruses; pre-latent phase; tumor microenvironment (TME).

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Conflict of interest statement

The authors declare no conflict of interest. The funders had no role in the writing of the manuscript.

Figures

Figure 1
Figure 1
Illustration of germinal center (GC) reaction indicating the events required for affinity maturation of antibody responses, the potential role of the EBV dUTPase protein in this process, and the cellular origins of various EBV-associated B- and T-cell lymphomas. DC = dendritic cell; SHN = somatic hypermutation; CSR = class-switch recombination; TFH = follicular CD4+ helper T cell.
Figure 2
Figure 2
Illustration of a naïve B cell infected by EBV and the role that EBV genes expressed during the pre-latent phase have in modulating cellular functions, such as immune evasion cell proliferation and apoptosis. The pre-latent phase is reported to occur seven to twenty-eight days following infection and continues until the EBV genome is hypermethylated.
Figure 3
Figure 3
Schematic diagram showing actions of the EBV dUTPase protein contributing to the development of follicular T cells and the subsequent production of IL-21 during the pre-latent phase.
Figure 4
Figure 4
Potential roles of EBV dUTPase in modulating the TME through activation of immune cells (DCs, macrophages, NKT) and secretion of proinflammatory cytokines, promoting TAM formation, T cell exhaustion, aberrant germinal center TFH function, and polyreactive antibodies production, which together can contribute to the TME and promote tumor progression. Dashed arrow represents an unproven process.
See this image and copyright information in PMC

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