Widespread activation of antisense transcription of the host genome during Herpes simplex virus 1 infection
Ontology highlight
ABSTRACT:
ORGANISM(S): Homo sapiens
PROVIDER: GSE97009 | GEO | 2017/09/28
SECONDARY ACCESSION(S): PRJNA380401
REPOSITORIES: GEO
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Project description:Infection by viruses, including Herpes Simplex virus-1 (HSV-1), and cellular stresses cause widespread disruption of transcription termination (DoTT) of RNA polymerase II (RNAPII). The underlying mechanisms, however, remain unclear. Here we demonstrate that, in HSV-1-infected cells, the viral immediate early factor ICP27 is necessary and sufficient for inducing DoTT. Mechanistically, ICP27 directly binds to the essential mRNA 3’ processing factor CPSF, induces the assembly of a dead-end 3’ processing complex, and blocks mRNA cleavage. Remarkably, ICP27 also acts as a sequence-dependent activator of mRNA 3’ processing for HSV-1 and a subset of host genes. Our results suggest that the bimodal activities of ICP27 play a key role in HSV-1-induced host shutoff and that CPSF is a common host factor targeted by multiple viruses. The mechanism described here may have implications for understanding other virus- and cell stress-mediated regulation of transcription termination.
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Project description:Chronic viral infections are difficult to treat and new approaches, particularly those involving enhancing immune responses are needed. Herpes simplex virus (HSV) establishes latency, reactivates frequently, and breakthrough reactivation can occur despite suppressive antiviral therapy. Virus-specific T cells are important to control HSV, and activated T cells require increased metabolism of glutamine for their proliferation. We found that treatment of HSV-1 latently infected mice and HSV-2 infected guinea pigs with supplemental oral glutamine reduced virus reactivation. Transcriptome analysis of mice treated with glutamine showed that several interferon (IFN)-γ inducible genes were upregulated. Unlike wild-type mice, supplemental glutamine was ineffective in reducing the rate of HSV-1 reactivation in IFN-γ knock-out mice. Mice treated with glutamine had higher numbers of HSV-specific IFN-γ producing CD8 T cells in latently infected ganglia. Thus, glutamine may enhance the IFN-γ-associated immune response and reduce the rate of reactivation of latent virus infection.
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Project description:Chronic viral infections are difficult to treat and new approaches, particularly those involving enhancing immune responses are needed. Herpes simplex virus (HSV) establishes latency, reactivates frequently, and breakthrough reactivation can occur despite suppressive antiviral therapy. Virus-specific T cells are important to control HSV, and activated T cells require increased metabolism of glutamine for their proliferation. We found that treatment of HSV-1 latently infected mice and HSV-2 infected guinea pigs with supplemental oral glutamine reduced virus reactivation. Transcriptome analysis of mice treated with glutamine showed that several interferon (IFN)-γ inducible genes were upregulated. Unlike wild-type mice, supplemental glutamine was ineffective in reducing the rate of HSV-1 reactivation in IFN-γ knock-out mice. Mice treated with glutamine had higher numbers of HSV-specific IFN-γ producing CD8 T cells in latently infected ganglia. Thus, glutamine may enhance the IFN-γ-associated immune response and reduce the rate of reactivation of latent virus infection.
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