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Journal of Virology, October 2009, p. 10644-10652, Vol. 83, No. 20
0022-538X/09/$08.00+0     doi:10.1128/JVI.01017-09
Copyright © 2009, American Society for Microbiology. All Rights Reserved.

A Gammaherpesvirus Ubiquitin-Specific Protease Is Involved in the Establishment of Murine Gammaherpesvirus 68 Infection {triangledown}

Sara Gredmark-Russ ,{dagger},{ddagger} Marisa K. Isaacson,{ddagger} Lisa Kattenhorn, Evelyn J. Cheung, Nicki Watson, and Hidde L. Ploegh*

Whitehead Institute for Biomedical Research, 9 Cambridge Center, Cambridge, Massachusetts 02142

Received 19 May 2009/ Accepted 3 August 2009

Murine gammaherpesvirus 68 (MHV-68) contains a ubiquitin (Ub)-specific cysteine protease (USP) domain embedded within the large tegument protein ORF64, as do all other herpesviruses. The biological role of this protease is still unclear, but for the alphaherpesvirus Marek's disease virus, its USP is involved in T-cell lymphoma formation. We here study the role of the MHV-68 USP, encoded by ORF64. By constructing a mutant virus with a single cysteine-to-alanine replacement in the active site of ORF64, we demonstrate that the USP activity of ORF64 is abolished. The mutant virus replicates less efficiently in vitro, and plaque size is reduced compared to that of a revertant virus. Electron microscopy of infected cells did not reveal any obvious differences in virion morphogenesis or differences in egress for the mutant and revertant viruses. Intraperitoneal infection of C57/BL6 mice demonstrates that the mutant virus is generally cleared by day 7, indicating a role for the USP in the persistence of MHV-68 infection or efficient replication. However, the USP activity in MHV-68 is unlikely to be involved in the establishment of latency or reactivation, since we observed no significant difference in viral DNA genome copy number in the spleen or in the number of cells that reactivate MHV-68 from latency. Our results for MHV-68 ORF64 are consistent with an enzymatic function of the tegument protein that is beneficial to the virus during acute infection, particularly in vivo.

* Corresponding author. Mailing address: Whitehead Institute for Biomedical Research, 9 Cambridge Center, Cambridge, MA 02142. Phone: (617) 324-1878. Fax: (617) 452-3566. E-mail: ploegh{at}wi.mit.edu

{triangledown} Published ahead of print on 12 August 2009.

{dagger} Present address: Center for Infectious Medicine, Department of Medicine, Karolinska Institutet, Karolinska University Hospital Huddinge, Stockholm, Sweden.

{ddagger} S.G.-R. and M.K.I. contributed equally to this work.

Journal of Virology, October 2009, p. 10644-10652, Vol. 83, No. 20
0022-538X/09/$08.00+0     doi:10.1128/JVI.01017-09
Copyright © 2009, American Society for Microbiology. All Rights Reserved.





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