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Induction of the Lytic Cycle Sensitizes Epstein-Barr Virus-Infected B Cells to NK Cell Killing That Is Counteracted by Virus-Mediated NK Cell Evasion Mechanisms in the Late Lytic Cycle.
J Virol. 2016 01 15; 90(2):947-58.JV

Abstract

Epstein-Barr Virus (EBV) persists for the lifetime of the infected host despite eliciting strong immune responses. This persistence requires a fine balance between the host immune system and EBV immune evasion. Accumulating evidence suggests an important role for natural killer (NK) cells in this balance. NK cells can kill EBV-infected cells undergoing lytic replication in vitro, and studies in both humans and mice with reconstituted human immune systems have shown that NK cells can limit EBV replication and prevent infectious mononucleosis. We now show that NK cells, via NKG2D and DNAM-1 interactions, recognize and kill EBV-infected cells undergoing lytic replication and that expression of a single EBV lytic gene, BZLF1, is sufficient to trigger sensitization to NK cell killing. We also present evidence suggesting the possibility of the existence of an as-yet-unidentified DNAM-1 ligand which may be particularly important for killing lytically infected normal B cells. Furthermore, while cells entering the lytic cycle become sensitized to NK cell killing, we observed that cells in the late lytic cycle are highly resistant. We identified expression of the vBcl-2 protein, BHRF1, as one effective mechanism by which EBV mediates this protection. Thus, contrary to the view expressed in some reports, EBV has evolved the ability to evade NK cell responses.

IMPORTANCE

This report extends our understanding of the interaction between EBV and host innate responses. It provides the first evidence that the susceptibility to NK cell lysis of EBV-infected B cells undergoing lytic replication is dependent upon the phase of the lytic cycle. Induction of the lytic cycle is associated with acquired sensitization to NK cell killing, while progress through the late lytic cycle is associated with acquired resistance to killing. We provide mechanistic explanations for this novel observation, indicating important roles for the BZLF1 immediate early transactivator, the BHRF1 vBcl-2 homologue, and a novel ligand for the DNAM-1 NK cell receptor.

Authors+Show Affiliations

Institute of Immunology & Immunotherapy, College of Medical & Dental Sciences, University of Birmingham, Birmingham, United Kingdom.Institute of Immunology & Immunotherapy, College of Medical & Dental Sciences, University of Birmingham, Birmingham, United Kingdom.Institute of Immunology & Immunotherapy, College of Medical & Dental Sciences, University of Birmingham, Birmingham, United Kingdom.Institute of Immunology & Immunotherapy, College of Medical & Dental Sciences, University of Birmingham, Birmingham, United Kingdom J.Zuo@bham.ac.uk.

Pub Type(s)

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

Language

eng

PubMed ID

26537677

Citation

Williams, Luke R., et al. "Induction of the Lytic Cycle Sensitizes Epstein-Barr Virus-Infected B Cells to NK Cell Killing That Is Counteracted By Virus-Mediated NK Cell Evasion Mechanisms in the Late Lytic Cycle." Journal of Virology, vol. 90, no. 2, 2016, pp. 947-58.
Williams LR, Quinn LL, Rowe M, et al. Induction of the Lytic Cycle Sensitizes Epstein-Barr Virus-Infected B Cells to NK Cell Killing That Is Counteracted by Virus-Mediated NK Cell Evasion Mechanisms in the Late Lytic Cycle. J Virol. 2016;90(2):947-58.
Williams, L. R., Quinn, L. L., Rowe, M., & Zuo, J. (2016). Induction of the Lytic Cycle Sensitizes Epstein-Barr Virus-Infected B Cells to NK Cell Killing That Is Counteracted by Virus-Mediated NK Cell Evasion Mechanisms in the Late Lytic Cycle. Journal of Virology, 90(2), 947-58. https://doi.org/10.1128/JVI.01932-15
Williams LR, et al. Induction of the Lytic Cycle Sensitizes Epstein-Barr Virus-Infected B Cells to NK Cell Killing That Is Counteracted By Virus-Mediated NK Cell Evasion Mechanisms in the Late Lytic Cycle. J Virol. 2016 01 15;90(2):947-58. PubMed PMID: 26537677.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - Induction of the Lytic Cycle Sensitizes Epstein-Barr Virus-Infected B Cells to NK Cell Killing That Is Counteracted by Virus-Mediated NK Cell Evasion Mechanisms in the Late Lytic Cycle. AU - Williams,Luke R, AU - Quinn,Laura L, AU - Rowe,Martin, AU - Zuo,Jianmin, Y1 - 2015/11/04/ PY - 2015/08/04/received PY - 2015/10/26/accepted PY - 2015/11/6/entrez PY - 2015/11/6/pubmed PY - 2016/5/12/medline SP - 947 EP - 58 JF - Journal of virology JO - J Virol VL - 90 IS - 2 N2 - UNLABELLED: Epstein-Barr Virus (EBV) persists for the lifetime of the infected host despite eliciting strong immune responses. This persistence requires a fine balance between the host immune system and EBV immune evasion. Accumulating evidence suggests an important role for natural killer (NK) cells in this balance. NK cells can kill EBV-infected cells undergoing lytic replication in vitro, and studies in both humans and mice with reconstituted human immune systems have shown that NK cells can limit EBV replication and prevent infectious mononucleosis. We now show that NK cells, via NKG2D and DNAM-1 interactions, recognize and kill EBV-infected cells undergoing lytic replication and that expression of a single EBV lytic gene, BZLF1, is sufficient to trigger sensitization to NK cell killing. We also present evidence suggesting the possibility of the existence of an as-yet-unidentified DNAM-1 ligand which may be particularly important for killing lytically infected normal B cells. Furthermore, while cells entering the lytic cycle become sensitized to NK cell killing, we observed that cells in the late lytic cycle are highly resistant. We identified expression of the vBcl-2 protein, BHRF1, as one effective mechanism by which EBV mediates this protection. Thus, contrary to the view expressed in some reports, EBV has evolved the ability to evade NK cell responses. IMPORTANCE: This report extends our understanding of the interaction between EBV and host innate responses. It provides the first evidence that the susceptibility to NK cell lysis of EBV-infected B cells undergoing lytic replication is dependent upon the phase of the lytic cycle. Induction of the lytic cycle is associated with acquired sensitization to NK cell killing, while progress through the late lytic cycle is associated with acquired resistance to killing. We provide mechanistic explanations for this novel observation, indicating important roles for the BZLF1 immediate early transactivator, the BHRF1 vBcl-2 homologue, and a novel ligand for the DNAM-1 NK cell receptor. SN - 1098-5514 UR - https://www.unboundmedicine.com/medline/citation/26537677/Induction_of_the_Lytic_Cycle_Sensitizes_Epstein_Barr_Virus_Infected_B_Cells_to_NK_Cell_Killing_That_Is_Counteracted_by_Virus_Mediated_NK_Cell_Evasion_Mechanisms_in_the_Late_Lytic_Cycle_ L2 - http://jvi.asm.org/cgi/pmidlookup?view=long&pmid=26537677 DB - PRIME DP - Unbound Medicine ER -