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Journal of Virology, August 2004, p. 8411-8420, Vol. 78, No. 16
0022-538X/04/$08.00+0     DOI: 10.1128/JVI.78.16.8411-8420.2004
Copyright © 2004, American Society for Microbiology. All Rights Reserved.

Herpes Simplex Virus 1 Has Multiple Mechanisms for Blocking Virus-Induced Interferon Production

Gregory T. Melroe,1 Neal A. DeLuca,2 and David M. Knipe1*

Department of Microbiology and Molecular Genetics, Harvard Medical School, Boston, Massachusetts,1 Department of Molecular Genetics and Biochemistry, University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania2

Received 4 February 2004/ Accepted 6 April 2004

In response to viral infection, host cells elicit a number of responses, including the expression of alpha/beta interferon (IFN-{alpha}/ß). In these cells, IFN regulatory factor-3 (IRF-3) undergoes a sequence of posttranslational modifications that allow it to act as a potent transcriptional coactivator of specific IFN genes, including IFN-ß. We investigated the mechanisms by which herpes simplex virus 1 (HSV-1) inhibits the production of IFN-ß mediated by the IRF-3 signaling pathway. Here, we show that HSV-1 infection can block the accumulation of IFN-ß triggered by Sendai virus (SeV) infection. Our results indicate that HSV-1 infection blocks the nuclear accumulation of activated IRF-3 but does not block the initial virus-induced phosphorylation of IRF-3. The former effect was at least partly mediated by increased turnover of IRF-3 in HSV-1-infected cells. Using mutant viruses, we determined that the immediate-early protein ICP0 was necessary for the inhibition of IRF-3 nuclear accumulation. Expression of ICP0 also had the ability to reduce IFN-ß production induced by SeV infection. ICP0 has been shown previously to play a role in HSV-1 sensitivity to IFN and in the inhibition of antiviral gene production. However, we observed that an ICP0 mutant virus still retained the ability to inhibit the production of IFN-ß. These results argue that HSV-1 has multiple mechanisms to inhibit the production of IFN-ß, providing additional ways in which HSV-1 can block the IFN-mediated host response.

* Corresponding author. Mailing address: Department of Microbiology and Molecular Genetics, Harvard Medical School, 200 Longwood Ave., Boston, MA 02115. Phone: (617) 432-1934. Fax: (617) 432-0223. E-mail: david_knipe{at}hms.harvard.edu.

Journal of Virology, August 2004, p. 8411-8420, Vol. 78, No. 16
0022-538X/04/$08.00+0     DOI: 10.1128/JVI.78.16.8411-8420.2004
Copyright © 2004, American Society for Microbiology. All Rights Reserved.



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