Evasion of Cellular Antiviral Responses by Human Cytomegalovirus TRS1 and IRS1

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

Research output: Contribution to journalArticle

114 Citations (Scopus)

Abstract

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 (VVΔE3L). HCMV also prevents the phosphorylation of the eukaryotic translation initiation factor eIF-2α, the activation of RNase L, and the shutoff of viral and cellular protein synthesis that otherwise result from VVΔE3L infection. To identify the HCMV gene(s) responsible for these effects, we prepared a library of VVΔE3L 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 VVΔE3L. The fragment comprises the 3′ end of the J1S open reading frame through the entire TRS1 gene. Analyses of additional VVΔE3L recombinants revealed that the protein encoded by TRS1, pTRS1, as well as the closely related IRS1 gene, rescues VVΔE3L replication and prevent the shutoff of protein synthesis, the phosphorylation of eIF-2α, and activation of RNase L. These results demonstrate that TRS1 and IRS1 are able to counteract critical host cell antiviral response pathways.

Original languageEnglish (US)
Pages (from-to)197-205
Number of pages9
JournalJournal of Virology
Volume78
Issue number1
DOIs
StatePublished - Jan 2004
Externally publishedYes

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Human herpesvirus 5
Cytomegalovirus
Antiviral Agents
protein synthesis
Viral Proteins
translation (genetics)
phosphorylation
Genes
Libraries
genes
Prokaryotic Initiation Factor-2
Phosphorylation
Vaccinia virus
RNA-binding proteins
Eukaryotic Initiation Factors
viral proteins
double-stranded RNA
cells
RNA-Binding Proteins
recombinant proteins

ASJC Scopus subject areas

  • Immunology

Cite this

Evasion of Cellular Antiviral Responses by Human Cytomegalovirus TRS1 and IRS1. / Child, Stephanie J.; Hakki, Morgan; De Niro, Katherine L.; Geballe, Adam P.

In: Journal of Virology, Vol. 78, No. 1, 01.2004, p. 197-205.

Research output: Contribution to journalArticle

Child, Stephanie J. ; Hakki, Morgan ; De Niro, Katherine L. ; Geballe, Adam P. / Evasion of Cellular Antiviral Responses by Human Cytomegalovirus TRS1 and IRS1. In: Journal of Virology. 2004 ; Vol. 78, No. 1. pp. 197-205.
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