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Journal of Virology, February 2004, p. 1706-1717, Vol. 78, No. 4
0022-538X/04/$08.00+0     DOI: 10.1128/JVI.78.4.1706-1717.2004
Copyright © 2004, American Society for Microbiology. All Rights Reserved.

Innate Cellular Response to Virus Particle Entry Requires IRF3 but Not Virus Replication

Susan E. Collins,1 Ryan S. Noyce,2 and Karen L. Mossman1,2*

Departments of Pathology and Molecular Medicine,1 Biochemistry, Centre for Gene Therapeutics, McMaster University, Hamilton, Ontario, Canada L8N 3Z52

Received 28 July 2003/ Accepted 21 October 2003

Mammalian cells respond to virus infections by eliciting both innate and adaptive immune responses. One of the most effective innate antiviral responses is the production of alpha/beta interferon and the subsequent induction of interferon-stimulated genes (ISGs), whose products collectively limit virus replication and spread. Following viral infection, interferon is produced in a biphasic fashion that involves a number of transcription factors, including the interferon regulatory factors (IRFs) 1, 3, 7, and 9. In addition, virus infection has been shown to directly induce ISGs in the absence of prior interferon production through the activation of IRF3. This process is believed to require virus replication and results in IRF3 hyperphosphorylation, nuclear localization, and proteasome-mediated degradation. Previously, we and others demonstrated that herpes simplex virus type 1 (HSV-1) induces ISGs and an antiviral response in fibroblasts in the absence of both interferon production and virus replication. In this report, we show that the entry of enveloped virus particles from diverse virus families elicits a similar innate response. This process requires IRF3, but not IRF1, IRF7, or IRF9. Following virus replication, the large DNA viruses HSV-1 and vaccinia virus effectively inhibit ISG mRNA accumulation, whereas the small RNA viruses Newcastle disease virus, Sendai virus, and vesicular stomatitis virus do not. In addition, we found that IRF3 hyperphosphorylation and degradation do not correlate with ISG and antiviral state induction but instead serve as a hallmark of productive virus replication, particularly following a high-multiplicity infection. Collectively, these data suggest that virus entry triggers an innate antiviral response mediated by IRF3 and that subsequent virus replication results in posttranslational modification of IRF3, such as hyperphosphorylation, depending on the nature of the incoming virus.

* Corresponding author. Mailing address: Department of Pathology and Molecular Medicine, Centre for Gene Therapeutics, Health Sciences Center Room 4H11, 1200 Main St. West, Hamilton, Ontario, Canada L8N 3Z5. Phone: (905) 525-9140, ext. 23542. Fax: (905) 522-6750. E-mail: mossk{at}mcmaster.ca.

Journal of Virology, February 2004, p. 1706-1717, Vol. 78, No. 4
0022-538X/04/$08.00+0     DOI: 10.1128/JVI.78.4.1706-1717.2004
Copyright © 2004, American Society for Microbiology. All Rights Reserved.



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