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Journal of Virology, January 2004, p. 197-205, Vol. 78, No. 1
0022-538X/04/$08.00+0     DOI: 10.1128/JVI.78.1.197-205.2004
Copyright © 2004, American Society for Microbiology. All Rights Reserved.

Evasion of Cellular Antiviral Responses by Human Cytomegalovirus TRS1 and IRS1

Stephanie J. Child, Morgan Hakki, Katherine L. De Niro, and Adam P. Geballe*

Divisions of Human Biology and Clinical Research, Fred Hutchinson Cancer Research Center, Seattle, Washington 98109-1024, and Departments of Microbiology and Medicine, University of Washington, Seattle, Washington 98115

Received 20 August 2003/ Accepted 16 September 2003

During infection with human cytomegalovirus (HCMV), cellular protein synthesis continues even as viral proteins are being synthesized in abundance. Thus, HCMV may have a mechanism for counteracting host cell antiviral pathways that act by shutting off translation. Consistent with this view, HCMV infection of human fibroblasts rescues the replication of a vaccinia virus mutant lacking the double-stranded RNA-binding protein gene E3L (VV{Delta}E3L). HCMV also prevents the phosphorylation of the eukaryotic translation initiation factor eIF-2{alpha}, the activation of RNase L, and the shutoff of viral and cellular protein synthesis that otherwise result from VV{Delta}E3L infection. To identify the HCMV gene(s) responsible for these effects, we prepared a library of VV{Delta}E3L recombinants containing HCMV genomic fragments. By infecting nonpermissive cells with this library and screening for VV gene expression and replication, we isolated a virus containing a 2.8-kb HCMV fragment that rescues replication of VV{Delta}E3L. The fragment comprises the 3' end of the J1S open reading frame through the entire TRS1 gene. Analyses of additional VV{Delta}E3L recombinants revealed that the protein encoded by TRS1, pTRS1, as well as the closely related IRS1 gene, rescues VV{Delta}E3L replication and prevent the shutoff of protein synthesis, the phosphorylation of eIF-2{alpha}, and activation of RNase L. These results demonstrate that TRS1 and IRS1 are able to counteract critical host cell antiviral response pathways.

* Corresponding author. Mailing address: Division of Human Biology, Fred Hutchinson Cancer Research Center, 1100 Fairview Ave. North, MS C2-023, P.O. Box 19024, Seattle, WA 98109-1024. Phone: (206) 667-5122. Fax: (206) 667-6523. E-mail: ageballe{at}fhcrc.org.

Journal of Virology, January 2004, p. 197-205, Vol. 78, No. 1
0022-538X/04/$08.00+0     DOI: 10.1128/JVI.78.1.197-205.2004
Copyright © 2004, American Society for Microbiology. All Rights Reserved.



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