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Herpes simplex host shutoff attenuates antiviral state

ABSTRACT: Herpes simplex virus mutants lacking the vhs gene are severely attenuated in animal models of pathogenesis and exhibit reduced growth in primary cell culture. As a result of these properties vhs-deleted virus have been proposed as live-attenuated viruses. Despite these findings and their implications for vacccines, the mechanisms by which vhs promotes infection in cell culture and in vivo are not understood. In this study we demonstrate that vhs-deficent viruses replicate to reduced levels in interferon(IFN)- primed cells. Furthermore, vhs-defective viruses induce increased levels of IFNβ and IFNβ-stimulated genes, and increased levels of eIF2α phosphorylation in infected cells. In addition, we demonstrate a generalized over-expression of viral RNAs following infection with a vhs-deficient virus. This suggests increased expression of IFN pathway inducing double stranded RNA, a potent pathogen-associated molecular pattern (PAMP). Together these data show that vhs likely functions to reduce innate immune responses and thereby acts as critical determinant of viral pathogenesis. Keywords: time course, genetic modification

ORGANISM(S): Mus musculus Human alphaherpesvirus 1

PROVIDER: GSE10962 | GEO | 2008/04/03

SECONDARY ACCESSION(S): PRJNA107163

REPOSITORIES: GEO

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Project description:Interferons (IFNs) are key players in the antiviral response. IFN sensing by the cell activates transcription of IFN-stimulated genes (ISGs) able to induce an antiviral state by affecting viral replication and release. IFN also induces the expression of ISGs that function as negative regulators to limit the strength and duration of IFN response. The ISGs identified so far belong to coding genes. However, only a small proportion of the transcriptome corresponds to coding transcripts and it has been estimated that there could be as many coding as long non-coding RNAs (lncRNAs). To address whether IFN can also regulate the expression of lncRNAs, we analyzed the transcriptome of HuH7 cells treated or not with IFNα2 by expression arrays. Analysis of the arrays showed increased levels of several well-characterized coding genes that respond to IFN both at early or late times. Furthermore, we identified several IFN-stimulated or -downregulated lncRNAs (ISRs and IDRs). Further validation showed that ISR2, 8, and 12 expression mimics that of their neighboring genes GBP1, IRF1, and IL6, respectively, all related to the IFN response. These genes are induced in response to different doses of IFNα2 in different cell lines at early (ISR2 or 8) or later (ISR12) time points. IFNβ also induced the expression of these lncRNAs. ISR2 and 8 were also induced by an influenza virus unable to block the IFN response but not by other wild-type lytic viruses tested. Surprisingly, both ISR2 and 8 were significantly upregulated in cultured cells and livers from patients infected with HCV. Increased levels of ISR2 were also detected in patients chronically infected with HIV. This is relevant as genome-wide guilt-by-association studies predict that ISR2, 8, and 12 may function in viral processes, in the IFN pathway and the antiviral response. Therefore, we propose that these lncRNAs could be induced by IFN to function as positive or negative regulators of the antiviral response. HuH7 cells were treated with 10000 units/ml of IFN a2 and RNA was isolated 3 days post-treatment

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Herpes simplex host shutoff attenuates antiviral state

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