Herpes Simplex Virus-1 (HSV-1) infection has been shown to be very resistant to the effects of the cellular interferon response. However, in the absence of viral gene expression HSV-1 induces the expression of cellular interferon-stimulated genes, possibly through activation of the interferon-regulatory factor 3 (IRF-3) cascade. The induction of IRF-3 by HSV-1 infection has not been well characterized. Using an HSV-1 mutant deficient in the expression of viral genes, we show that HSV-1 can induce the cascade of IRF-3 activation by stimulating the phosphorylation of IRF-3 and the nuclear localization of the protein. We will show that activation of this pathway leads to the expression of interferon-stimulated genes and the production of a protective antiviral response. Further we will show that the expression of one viral gene, ICP0, is essential and sufficient to the inhibition of interferon-stimulated gene expression. An HSV-1 mutant deficient in expression of all immediate-early HSV-1 genes except ICP0 does not induce nuclear accumulation of IRF-3 and does not induce the expression of interferon-stimulated genes. This virus induces the mis-localization of the kinase (TBK-1) responsible for the phosphorylation of IRF-3. Cytoplasmically localized ICP0 expressed in wild-type infection stimulates the translocation of TBK-1 from the cytoplasm to the Golgi apparatus. This ICP0-mediated mis-localization, as well as a portion of that induced by the ICP0 expressing mutant, can be inhibited through the inhibition of the proteasome. Further, IRF-3 nuclear translocation and interferon-stimulated gene expression can be restored during infection with the ICP0-expressing mutant virus in the presence of proteasome inhibitors. This study explores the induction of the interferon regulatory factor-3 cellular antiviral response pathway, and presents a possible mechanism for the virus' resistance to the cellular antiviral response.
| Identifer | oai:union.ndltd.org:PITT/oai:PITTETD:etd-11142006-204506 |
| Date | 30 November 2006 |
| Creators | Eidson, Kasey Michelle |
| Contributors | Neal DeLuca, Saleem Khan, Thomas Smithgall, Paul Kinchington, Fred Homa |
| Publisher | University of Pittsburgh |
| Source Sets | University of Pittsburgh |
| Language | English |
| Detected Language | English |
| Type | text |
| Format | application/pdf |
| Source | http://etd.library.pitt.edu/ETD/available/etd-11142006-204506/ |
| Rights | unrestricted, I hereby certify that, if appropriate, I have obtained and attached hereto a written permission statement from the owner(s) of each third party copyrighted matter to be included in my thesis, dissertation, or project report, allowing distribution as specified below. I certify that the version I submitted is the same as that approved by my advisory committee. I hereby grant to University of Pittsburgh or its agents the non-exclusive license to archive and make accessible, under the conditions specified below, my thesis, dissertation, or project report in whole or in part in all forms of media, now or hereafter known. I retain all other ownership rights to the copyright of the thesis, dissertation or project report. I also retain the right to use in future works (such as articles or books) all or part of this thesis, dissertation, or project report. |
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