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Epstein-Barr Virus BZLF1-Mediated Downregulation of Proinflammatory Factors Is Essential for Optimal Lytic Viral Replication.
J Virol. 2016 01 15; 90(2):887-903.JV

Abstract

Elevated secretion of inflammatory factors is associated with latent Epstein-Barr virus (EBV) infection and the pathology of EBV-associated diseases; however, knowledge of the inflammatory response and its biological significance during the lytic EBV cycle remains elusive. Here, we demonstrate that the immediate early transcriptional activator BZLF1 suppresses the proinflammatory factor tumor necrosis factor alpha (TNF-α) by binding to the promoter of TNF-α and preventing NF-κB activation. A BZLF1Δ207-210 mutant with a deletion of 4 amino acids (aa) in the protein-protein binding domain was not able to inhibit the proinflammatory factors TNF-α and gamma interferon (IFN-γ) and reduced viral DNA replication with complete transcriptional activity during EBV lytic gene expression. TNF-α depletion restored the viral replication mediated by BZLF1Δ207-210. Furthermore, a combination of TNF-α- and IFN-γ-neutralizing antibodies recovered BZLF1Δ207-210-mediated viral replication, indicating that BZLF1 attenuates the antiviral response to aid optimal lytic replication primarily through the inhibition of TNF-α and IFN-γ secretion during the lytic cycle. These results suggest that EBV BZLF1 attenuates the proinflammatory responses to facilitate viral replication.

IMPORTANCE

The proinflammatory response is an antiviral and anticancer strategy following the complex inflammatory phenotype. Latent Epstein-Barr virus (EBV) infection strongly correlates with an elevated secretion of inflammatory factors in a variety of severe diseases, while the inflammatory responses during the lytic EBV cycle have not been established. Here, we demonstrate that BZLF1 acts as a transcriptional suppressor of the inflammatory factors TNF-α and IFN-γ and confirm that BZLF1-facilitated escape from the TNF-α and IFN-γ response during the EBV lytic life cycle is required for optimal viral replication. This finding implies that the EBV lytic cycle employs a distinct strategy to evade the antiviral inflammatory response.

Authors+Show Affiliations

Institute of Human Virology, Zhongshan School of Medicine, Sun Yat-sen University, Guangzhou, China Key Laboratory of Tropical Disease Control (Sun Yat-sen University), Ministry of Education, Guangzhou, China.Institute of Human Virology, Zhongshan School of Medicine, Sun Yat-sen University, Guangzhou, China.Institute of Human Virology, Zhongshan School of Medicine, Sun Yat-sen University, Guangzhou, China.Institute of Human Virology, Zhongshan School of Medicine, Sun Yat-sen University, Guangzhou, China.Institute of Human Virology, Zhongshan School of Medicine, Sun Yat-sen University, Guangzhou, China.Institute of Human Virology, Zhongshan School of Medicine, Sun Yat-sen University, Guangzhou, China Guanghua School of Stomatology, Sun Yat-sen University, Guangzhou, China.German Cancer Research Centre (DKFZ), Unit F100, Heidelberg, Germany.Institute of Human Virology, Zhongshan School of Medicine, Sun Yat-sen University, Guangzhou, China Key Laboratory of Tropical Disease Control (Sun Yat-sen University), Ministry of Education, Guangzhou, China kuangersh@mail.sysu.edu.cn.

Pub Type(s)

Journal Article
Research Support, Non-U.S. Gov't

Language

eng

PubMed ID

26537683

Citation

Li, Yuqing, et al. "Epstein-Barr Virus BZLF1-Mediated Downregulation of Proinflammatory Factors Is Essential for Optimal Lytic Viral Replication." Journal of Virology, vol. 90, no. 2, 2016, pp. 887-903.
Li Y, Long X, Huang L, et al. Epstein-Barr Virus BZLF1-Mediated Downregulation of Proinflammatory Factors Is Essential for Optimal Lytic Viral Replication. J Virol. 2016;90(2):887-903.
Li, Y., Long, X., Huang, L., Yang, M., Yuan, Y., Wang, Y., Delecluse, H. J., & Kuang, E. (2016). Epstein-Barr Virus BZLF1-Mediated Downregulation of Proinflammatory Factors Is Essential for Optimal Lytic Viral Replication. Journal of Virology, 90(2), 887-903. https://doi.org/10.1128/JVI.01921-15
Li Y, et al. Epstein-Barr Virus BZLF1-Mediated Downregulation of Proinflammatory Factors Is Essential for Optimal Lytic Viral Replication. J Virol. 2016 01 15;90(2):887-903. PubMed PMID: 26537683.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - Epstein-Barr Virus BZLF1-Mediated Downregulation of Proinflammatory Factors Is Essential for Optimal Lytic Viral Replication. AU - Li,Yuqing, AU - Long,Xubing, AU - Huang,Lu, AU - Yang,Mengtian, AU - Yuan,Yan, AU - Wang,Yan, AU - Delecluse,Henri-Jacques, AU - Kuang,Ersheng, Y1 - 2015/11/04/ PY - 2015/07/29/received PY - 2015/10/19/accepted PY - 2015/11/6/entrez PY - 2015/11/6/pubmed PY - 2016/5/12/medline SP - 887 EP - 903 JF - Journal of virology JO - J Virol VL - 90 IS - 2 N2 - UNLABELLED: Elevated secretion of inflammatory factors is associated with latent Epstein-Barr virus (EBV) infection and the pathology of EBV-associated diseases; however, knowledge of the inflammatory response and its biological significance during the lytic EBV cycle remains elusive. Here, we demonstrate that the immediate early transcriptional activator BZLF1 suppresses the proinflammatory factor tumor necrosis factor alpha (TNF-α) by binding to the promoter of TNF-α and preventing NF-κB activation. A BZLF1Δ207-210 mutant with a deletion of 4 amino acids (aa) in the protein-protein binding domain was not able to inhibit the proinflammatory factors TNF-α and gamma interferon (IFN-γ) and reduced viral DNA replication with complete transcriptional activity during EBV lytic gene expression. TNF-α depletion restored the viral replication mediated by BZLF1Δ207-210. Furthermore, a combination of TNF-α- and IFN-γ-neutralizing antibodies recovered BZLF1Δ207-210-mediated viral replication, indicating that BZLF1 attenuates the antiviral response to aid optimal lytic replication primarily through the inhibition of TNF-α and IFN-γ secretion during the lytic cycle. These results suggest that EBV BZLF1 attenuates the proinflammatory responses to facilitate viral replication. IMPORTANCE: The proinflammatory response is an antiviral and anticancer strategy following the complex inflammatory phenotype. Latent Epstein-Barr virus (EBV) infection strongly correlates with an elevated secretion of inflammatory factors in a variety of severe diseases, while the inflammatory responses during the lytic EBV cycle have not been established. Here, we demonstrate that BZLF1 acts as a transcriptional suppressor of the inflammatory factors TNF-α and IFN-γ and confirm that BZLF1-facilitated escape from the TNF-α and IFN-γ response during the EBV lytic life cycle is required for optimal viral replication. This finding implies that the EBV lytic cycle employs a distinct strategy to evade the antiviral inflammatory response. SN - 1098-5514 UR - https://www.unboundmedicine.com/medline/citation/26537683/Epstein_Barr_Virus_BZLF1_Mediated_Downregulation_of_Proinflammatory_Factors_Is_Essential_for_Optimal_Lytic_Viral_Replication_ L2 - http://jvi.asm.org/cgi/pmidlookup?view=long&pmid=26537683 DB - PRIME DP - Unbound Medicine ER -