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Journal of Virology, August 2006, p. 8006-8018, Vol. 80, No. 16
0022-538X/06/$08.00+0     doi:10.1128/JVI.00743-06
Copyright © 2006, American Society for Microbiology. All Rights Reserved.

Evidence for a Role of the Cellular ND10 Protein PML in Mediating Intrinsic Immunity against Human Cytomegalovirus Infections

Nina Tavalai, Peer Papior, Sabine Rechter, Martina Leis, and Thomas Stamminger*

Institut für Klinische und Molekulare Virologie der Universität Erlangen-Nürnberg, Schlossgarten 4, 91054 Erlangen, Germany

Received 12 April 2006/ Accepted 30 May 2006

Several viruses, including human cytomegalovirus (HCMV), encode proteins that colocalize with a cellular subnuclear structure known as ND10. Since only viral DNA deposited at ND10 initiates transcription, ND10 structures were hypothesized to be essential for viral replication. On the other hand, interferon treatment induces an up-regulation of ND10 structures and viruses have evolved polypeptides that disperse the dot-like accumulation of ND10 proteins, suggesting that ND10 could also be part of an intrinsic defense mechanism. In order to obtain evidence for either a proviral or an antiviral function of ND10, we generated primary human fibroblasts with a stable, short interfering RNA-mediated knockdown (kd) of PML. In these cells, other ND10-associated proteins like hDaxx showed a diffuse nuclear distribution. Interestingly, we observed that HCMV infection induced the de novo formation of ND10-like hDaxx and Sp100 accumulations that colocalized with IE2 and were disrupted, in the apparent absence of PML, in an IE1-dependent manner during the first hours after infection. Furthermore, infection of PML-kd cells with wild-type HCMV at a low multiplicity of infection resulted in enhanced replication. In particular, a significantly increased plaque formation was detected, suggesting that more cells are able to support initiation of replication in the absence of PML. While there was no difference in viral DNA uptake between PML-kd and control cells, we observed a considerable increase in the number of immediate-early (IE) protein-positive cells, indicating that the depletion of PML augments the initiation of viral IE gene expression. These results strongly suggest that PML functions as part of an intrinsic immune mechanism against cytomegalovirus infections.

* Corresponding author. Mailing address: Institut für Klinische und Molekulare Virologie der Universität Erlangen-Nürnberg, Schlossgarten 4, 91054 Erlangen, Germany. Phone: 49 9131 852 6783. Fax: 49 9131 852 2101. E-mail: thomas.stamminger{at}viro.med.uni-erlangen.de.

Journal of Virology, August 2006, p. 8006-8018, Vol. 80, No. 16
0022-538X/06/$08.00+0     doi:10.1128/JVI.00743-06
Copyright © 2006, American Society for Microbiology. All Rights Reserved.



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