The Induction and Inhibition of an Antiviral Response by Herpes Simplex Virus 1

[摘要] 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.

[发布机构] the University of Pittsburgh

[效力级别] d109