This Article
Right arrow Full Text
Right arrow Full Text (PDF)
Right arrow Supplemental material
Right arrow Alert me when this article is cited
Right arrow Alert me if a correction is posted
Services
Right arrow Similar articles in this journal
Right arrow Similar articles in PubMed
Right arrow Alert me to new issues of the journal
Right arrow Download to citation manager
Right arrowReprints and Permissions
Right arrow Copyright Information
Right arrow Books from ASM Press
Right arrow MicrobeWorld
Citing Articles
Right arrow Citing Articles via Google Scholar
Google Scholar
Right arrow Articles by Marshall, E. E.
Right arrow Articles by Geballe, A. P.
Right arrow Search for Related Content
PubMed
Right arrow PubMed Citation
Right arrow Articles by Marshall, E. E.
Right arrow Articles by Geballe, A. P.

 Previous Article  |  Next Article 

Journal of Virology, May 2009, p. 4112-4120, Vol. 83, No. 9
0022-538X/09/$08.00+0     doi:10.1128/JVI.02489-08
Copyright © 2009, American Society for Microbiology. All Rights Reserved.

Essential Role for either TRS1 or IRS1 in Human Cytomegalovirus Replication{triangledown} ,{dagger}

Emily E. Marshall,1,4 Craig J. Bierle,3,4 Wolfram Brune,6 and Adam P. Geballe1,2,4,5*

Departments of Microbiology,1 Medicine,2 Program in Molecular and Cellular Biology, University of Washington, Seattle, Washington 98115,3 Divisions of Human Biology,4 Clinical Research, Fred Hutchinson Cancer Research Center, Seattle, Washington 98109,5 Division of Viral Infections, Robert Koch-Institute, Nordufer 20, 13353 Berlin, Germany6

Received 3 December 2008/ Accepted 3 February 2009

Viral infections often produce double-stranded RNA (dsRNA), which in turn triggers potent antiviral responses, including the global repression of protein synthesis mediated by protein kinase R (PKR) and 2'-5' oligoadenylate synthetase (OAS). As a consequence, many viruses have evolved genes, such as those encoding dsRNA-binding proteins, which counteract these pathways. Human cytomegalovirus (HCMV) encodes two related proteins, pTRS1 and pIRS1, which bind dsRNA and can prevent activation of the PKR and OAS pathways. HCMV mutants lacking either IRS1 or TRS1 replicate at least moderately well in cell culture. However, as we demonstrate in the present study, an HCMV mutant lacking both IRS1 and TRS1 (HCMV[{Delta}I/{Delta}T]) has a severe replication defect. Infection with HCMV[{Delta}I/{Delta}T] results in a profound inhibition of overall and viral protein synthesis, as well as increased phosphorylation of eukaryotic initiation factor 2{alpha} (eIF2{alpha}). The vaccinia virus E3L gene can substitute for IRS1 or TRS1, enabling HCMV replication. Despite the accumulation of dsRNA in HCMV-infected cells, the OAS pathway remains inactive, even in HCMV[{Delta}I/{Delta}T]-infected cells. These results suggest that PKR-mediated phosphorylation of eIF2{alpha} is the dominant dsRNA-activated pathway responsible for inhibition of protein synthesis and HCMV replication in the absence of both IRS1 and TRS1 and that the requirement for evasion of the PKR pathway likely explains the necessity for IRS1 or TRS1 for productive infection.

* Corresponding author. Mailing address: Division of Human Biology, Fred Hutchinson Cancer Research Center, 1100 Fairview Ave. N, MS C2-023, Seattle, WA 98109-1024. Phone: (206) 667-5122. Fax: (206) 667-6523. E-mail: ageballe{at}fhcrc.org

{triangledown} Published ahead of print on 11 February 2009.

{dagger} Supplemental material for this article may be found at http://jvi.asm.org/.

Journal of Virology, May 2009, p. 4112-4120, Vol. 83, No. 9
0022-538X/09/$08.00+0     doi:10.1128/JVI.02489-08
Copyright © 2009, American Society for Microbiology. All Rights Reserved.





Copyright © 2009 by the American Society for Microbiology.   For an alternate route to Journals.ASM.org, visit: http://intl-journals.asm.org | More Info»