A cancer-associated Epstein-Barr virus BZLF1 promoter variant enhances lytic infection
File(s)
Published version
Author(s)
Type
Journal Article
Abstract
Latent Epstein-Barr virus (EBV) infection contributes to both B-cell and epithelial-cell malignancies. However, whether lytic EBV infection also contributes to tumors is unclear, although the association between malaria infection and Burkitt lymphomas (BLs) may involve excessive lytic EBV replication. A particular variant of the viral promoter (Zp) that controls lytic EBV reactivation is over-represented, relative to its frequency in non-malignant tissue, in EBV-positive nasopharyngeal carcinomas and AIDS-related lymphomas. To date, no functional differences between the prototype Zp (Zp-P) and the cancer-associated variant (Zp-V3) have been identified. Here we show that a single nucleotide difference between the Zp-V3 and Zp-P promoters creates a binding site for the cellular transcription factor, NFATc1, in the Zp-V3 (but not Zp-P) variant, and greatly enhances Zp activity and lytic viral reactivation in response to NFATc1-inducing stimuli such as B-cell receptor activation and ionomycin. Furthermore, we demonstrate that restoring this NFATc1-motif to the Zp-P variant in the context of the intact EBV B95.8 strain genome greatly enhances lytic viral reactivation in response to the NFATc1-activating agent, ionomycin, and this effect is blocked by the NFAT inhibitory agent, cyclosporine, as well as NFATc1 siRNA. We also show that the Zp-V3 variant is over-represented in EBV-positive BLs and gastric cancers, and in EBV-transformed B-cell lines derived from EBV-infected breast milk of Kenyan mothers that had malaria during pregnancy. These results demonstrate that the Zp-V3 enhances EBV lytic reactivation to physiologically-relevant stimuli, and suggest that increased lytic infection may contribute to the increased prevalence of this variant in EBV-associated malignancies.
Date Issued
2018-07-27
Date Acceptance
2018-06-25
Citation
PLoS Pathogens, 2018, 14 (7)
ISSN
1553-7366
Publisher
Public Library of Science (PLoS)
Journal / Book Title
PLoS Pathogens
Volume
14
Issue
7
Copyright Statement
© 2018 Bristol et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.
Sponsor
Medical Research Council
Grant Number
MR/N010388/1
Subjects
Science & Technology
Life Sciences & Biomedicine
Microbiology
Parasitology
Virology
LYMPHOBLASTOID CELL-LINES
A-SENSITIVE INDUCTION
B-CELLS
GASTRIC-CARCINOMA
TRANSCRIPTION FACTOR
GENE-EXPRESSION
CONSTITUTIVE ACTIVATION
EPITHELIAL-CELLS
BURKITT-LYMPHOMA
VIRAL-INFECTION
0605 Microbiology
1107 Immunology
1108 Medical Microbiology
Publication Status
Published
Article Number
e1007179