Abstract
Herpes simplex viruses (HSV) are ubiquitous pathogens causing a variety of diseases ranging from mild illness to severe life-threatening infections. HSV utilize cellular signaling pathways and transcription factors to promote their replication. Here we report that HSV type 1 (HSV-1) induces persistent activation of transcription factor NF-kappa B, a critical regulator of genes involved in inflammation, by activating the I kappa B kinase (IKK) in the early phase of infection. Activated NF-kappa B enhances HSV-1 gene expression. HSV-1-induced NF-kappa B activation is dependent on viral early protein synthesis and is not blocked by the anti-herpetic drug acyclovir. IKK inhibition by the anti-inflammatory cyclopentenone prostaglandin A(1) blocks HSV-1 gene expression and reduces virus yield by more than 3000-fold. The results identify IKK as a potential target for anti-herpetic drugs and suggest that cyclopentenone prostaglandins or their derivatives could be used in the treatment of HSV infection.
MeSH terms
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Acyclovir / pharmacology
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Animals
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Anti-Inflammatory Agents, Non-Steroidal / pharmacology*
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Antiviral Agents / pharmacology
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Chlorocebus aethiops
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Cycloheximide / pharmacology
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Dactinomycin / pharmacology
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Drug Design
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Enzyme Activation
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Enzyme Inhibitors / pharmacology
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Gene Expression Regulation, Fungal / drug effects
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Gene Expression Regulation, Fungal / physiology*
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Herpesvirus 1, Human / drug effects
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Herpesvirus 1, Human / genetics
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Herpesvirus 1, Human / physiology*
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Humans
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I-kappa B Kinase
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Kinetics
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Laryngeal Neoplasms
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Methionine / metabolism
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NF-kappa B / metabolism*
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Neuroblastoma
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Prostaglandins A / pharmacology
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Protein Serine-Threonine Kinases / metabolism*
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Recombinant Proteins / metabolism
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Transfection
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Tumor Cells, Cultured
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Vero Cells
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Virus Replication / drug effects
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Virus Replication / physiology*
Substances
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Anti-Inflammatory Agents, Non-Steroidal
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Antiviral Agents
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Enzyme Inhibitors
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NF-kappa B
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Prostaglandins A
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Recombinant Proteins
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Dactinomycin
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Cycloheximide
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Methionine
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Protein Serine-Threonine Kinases
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CHUK protein, human
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I-kappa B Kinase
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IKBKB protein, human
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IKBKE protein, human
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prostaglandin A1
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Acyclovir