Imperial College London
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ProfessorPaulFarrell

Faculty of Medicine, Department of Infectious Disease

Professor of Tumour Virology
 
 
 
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Contact

 

+44 (0)20 7594 2005p.farrell Website

 
 
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Location

 

Section of VirologyNorfolk PlaceSt Mary's Campus

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Summary

 

Publications

Citation

BibTex format

@article{Bristol:2018:10.1371/journal.ppat.1007179,
author = {Bristol, J and Djavadian, R and Albright, E and Coleman, C and Ohashi, M and Hayes, M and Romero-Masters, J and Barlow, E and Farrell, PJ and Rochford, R and Kalejta, R and Johannsen, E and Kenney, S},
doi = {10.1371/journal.ppat.1007179},
journal = {PLoS Pathogens},
title = {A cancer-associated Epstein-Barr virus BZLF1 promoter variant enhances lytic infection},
url = {http://dx.doi.org/10.1371/journal.ppat.1007179},
volume = {14},
year = {2018}
}
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RIS format (EndNote, RefMan)

TY  - JOUR
AB  - 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.
AU  - Bristol,J
AU  - Djavadian,R
AU  - Albright,E
AU  - Coleman,C
AU  - Ohashi,M
AU  - Hayes,M
AU  - Romero-Masters,J
AU  - Barlow,E
AU  - Farrell,PJ
AU  - Rochford,R
AU  - Kalejta,R
AU  - Johannsen,E
AU  - Kenney,S
DO  - 10.1371/journal.ppat.1007179
PY  - 2018///
SN  - 1553-7366
TI  - A cancer-associated Epstein-Barr virus BZLF1 promoter variant enhances lytic infection
T2  - PLoS Pathogens
UR  - http://dx.doi.org/10.1371/journal.ppat.1007179
UR  - http://hdl.handle.net/10044/1/61804
VL  - 14
ER  -
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