Details

Autor(en) / Beteiligte

• Bristol, Jillian A
• Djavadian, Reza
• Albright, Emily R
• Coleman, Carrie B
• Ohashi, Makoto
• Hayes, Mitchell
• Romero-Masters, James C
• Barlow, Elizabeth A
• Farrell, Paul J
• Rochford, Rosemary
• Kalejta, Robert F
• Johannsen, Eric C
• Kenney, Shannon C
• Flemington, Erik K

Titel

A cancer-associated Epstein-Barr virus BZLF1 promoter variant enhances lytic infection

Ist Teil von

• PLoS pathogens, 2018-07, Vol.14 (7), p.e1007179

Ort / Verlag

United States: Public Library of Science

Erscheinungsjahr

2018

Quelle

EZB-FREE-00999 freely available EZB journals

Beschreibungen/Notizen

• 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.