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J. Virol. 87 (4): 2174-2185

Copyright © 2013 by the American Society for Microbiology. All rights reserved.

Components of Promyelocytic Leukemia Nuclear Bodies (ND10) Act Cooperatively To Repress Herpesvirus Infection

Mandy Glass, and Roger D. Everett

MRC-University of Glasgow Centre for Virus Research, Glasgow, Scotland, United Kingdom

Received for publication 19 October 2012. Accepted for publication 28 November 2012.

Abstract: Upon the entry of the viral genome into the nucleus, herpes simplex virus type 1 (HSV-1) gene expression is rapidly repressed by constitutively expressed cellular proteins. This intrinsic antiviral defense is normally counteracted by ICP0, which allows virus infection to proceed efficiently. Replication of ICP0-null mutant HSV-1, however, is severely repressed by mechanisms that are conferred, at least in part, by nuclear domain 10 (ND10) components, including hDaxx, the promyelocytic leukemia (PML) protein, and Sp100. To investigate if these ND10 components repress viral gene expression in a cooperative manner, we simultaneously depleted host cells for hDaxx, PML, and Sp100 by multiple short hairpin RNA (shRNA) knockdown from a single lentivirus vector. We found that replication and gene expression of ICP0-null mutant HSV-1 were cooperatively repressed by hDaxx, PML, and Sp100 immediately upon infection, and all stages of virus replication were inhibited. Plaque-forming efficiency was enhanced at least 50-fold in the triple-depleted cells, a much larger increase than achieved by depletion of any single ND10 protein. Similar effects were also observed during infection of triple-depleted cells with human cytomegalovirus (HCMV). Moreover, using a cell culture model of quiescent infection, we found that triple depletion resulted in a much larger number of viral genomes escaping repression. However, triple depletion was unable to fully overcome the ICP0-null phenotype, implying the presence of additional repressive host factors, possibly components of the SUMO modification or DNA repair pathways. We conclude that several ND10 components cooperate in an additive manner to regulate HSV-1 and HCMV infection.


Address correspondence to Roger D. Everett, roger.everett{at}glasgow.ac.uk.

Published ahead of print 5 December 2012


THIS ARTICLE HAS BEEN CITED BY OTHER ARTICLES:
Two Overlapping Regions within the N-Terminal Half of the Herpes Simplex Virus 1 E3 Ubiquitin Ligase ICP0 Facilitate the Degradation and Dissociation of PML and Dissociation of Sp100 from ND10.
M. Perusina Lanfranca, H. H. Mostafa, and D. J. Davido (2013)
J. Virol. 87, 13287-13296
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Nuclear interferon-inducible protein 16 promotes silencing of herpesviral and transfected DNA.
M. H. Orzalli, S. E. Conwell, C. Berrios, J. A. DeCaprio, and D. M. Knipe (2013)
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Sp100 Provides Intrinsic Immunity against Human Papillomavirus Infection.
W. H. Stepp, J. M. Meyers, and A. A. McBride (2013)
mBio 4, e00845-13
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Interaction of Herpes Simplex Virus ICP0 with ND10 Bodies: a Sequential Process of Adhesion, Fusion, and Retention.
H. Gu, Y. Zheng, and B. Roizman (2013)
J. Virol. 87, 10244-10254
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