Pharmacologic activation of Lytic Epstein-Barr Virus gene expression without virion production

Jaeyeun Lee, John G. Kosowicz, S. Diane Hayward, Prashant Desai, Jennifer Stone, Jae Myun Lee, Jun Liu, Richard F Ambinder

Research output: Contribution to journalArticle

Abstract

Several therapeutic strategies targeting Epstein-Barr virus (EBV)-associated tumors involve upregulation of viral lytic gene expression. Evidence has been presented that the unfolded protein response (UPR) leads to EBV lytic gene expression. Clofoctol, an antibacterial antibiotic, has been reported to upregulate the UPR in prostate cancer cell lines and to slow their growth. We investigated the effects of clofoctol on an EBV-positive Burkitt lymphoma cell line and confirmed the upregulation of all three branches of the UPR and activation of EBV lytic gene expression. While immediate early, early, and late EBV RNAs were all upregulated, immediate early and early viral proteins but not late viral proteins were expressed. Furthermore, infectious virions were not produced. The use of clofoctol in combination with a protein kinase R-like endoplasmic reticulum kinase inhibitor led to expression of late viral proteins. The effects of clofoctol on EBV lytic protein upregulation were not limited to lymphoid tumor cell lines but also occurred in naturally infected epithelial gastric cancer and nasopharyngeal cancer cell lines. An agent that upregulates lytic viral protein expression but that does not lead to the production of infectious virions may have particular value for lytic induction strategies in the clinical setting. IMPORTANCE Epstein-Barr virus is associated with many different cancers. In these cancers the viral genome is predominantly latent; i.e., most viral genes are not expressed, most viral proteins are not synthesized, and new virions are not produced. Some strategies for treating these cancers involve activation of lytic viral gene expression. We identify an antibacterial antibiotic, clofoctol, that is an activator of EBV lytic RNA and protein expression but that does not lead to virion production.

Original languageEnglish (US)
Article numbere00998-19
JournalJournal of virology
Volume93
Issue number20
DOIs
StatePublished - Oct 1 2019

Fingerprint

Human herpesvirus 4
Human Herpesvirus 4
virion
Virion
viral proteins
Viral Proteins
Gene Expression
gene expression
unfolded protein response
Up-Regulation
Unfolded Protein Response
Viral Genes
cell lines
neoplasms
Cell Line
Neoplasms
protein synthesis
antibiotics
RNA
Nasopharyngeal Neoplasms

Keywords

  • Epstein-Barr virus
  • Gastric carcinoma
  • Integrated stress response
  • Lymphoma
  • Nasopharyngeal carcinoma
  • Oncolytic viruses
  • Proteasome
  • Unfolded protein response

ASJC Scopus subject areas

  • Microbiology
  • Immunology
  • Insect Science
  • Virology

Cite this

Pharmacologic activation of Lytic Epstein-Barr Virus gene expression without virion production. / Lee, Jaeyeun; Kosowicz, John G.; Hayward, S. Diane; Desai, Prashant; Stone, Jennifer; Lee, Jae Myun; Liu, Jun; Ambinder, Richard F.

In: Journal of virology, Vol. 93, No. 20, e00998-19, 01.10.2019.

Research output: Contribution to journalArticle

Lee, Jaeyeun ; Kosowicz, John G. ; Hayward, S. Diane ; Desai, Prashant ; Stone, Jennifer ; Lee, Jae Myun ; Liu, Jun ; Ambinder, Richard F. / Pharmacologic activation of Lytic Epstein-Barr Virus gene expression without virion production. In: Journal of virology. 2019 ; Vol. 93, No. 20.
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abstract = "Several therapeutic strategies targeting Epstein-Barr virus (EBV)-associated tumors involve upregulation of viral lytic gene expression. Evidence has been presented that the unfolded protein response (UPR) leads to EBV lytic gene expression. Clofoctol, an antibacterial antibiotic, has been reported to upregulate the UPR in prostate cancer cell lines and to slow their growth. We investigated the effects of clofoctol on an EBV-positive Burkitt lymphoma cell line and confirmed the upregulation of all three branches of the UPR and activation of EBV lytic gene expression. While immediate early, early, and late EBV RNAs were all upregulated, immediate early and early viral proteins but not late viral proteins were expressed. Furthermore, infectious virions were not produced. The use of clofoctol in combination with a protein kinase R-like endoplasmic reticulum kinase inhibitor led to expression of late viral proteins. The effects of clofoctol on EBV lytic protein upregulation were not limited to lymphoid tumor cell lines but also occurred in naturally infected epithelial gastric cancer and nasopharyngeal cancer cell lines. An agent that upregulates lytic viral protein expression but that does not lead to the production of infectious virions may have particular value for lytic induction strategies in the clinical setting. IMPORTANCE Epstein-Barr virus is associated with many different cancers. In these cancers the viral genome is predominantly latent; i.e., most viral genes are not expressed, most viral proteins are not synthesized, and new virions are not produced. Some strategies for treating these cancers involve activation of lytic viral gene expression. We identify an antibacterial antibiotic, clofoctol, that is an activator of EBV lytic RNA and protein expression but that does not lead to virion production.",
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