Activation of I kappa b kinase by herpes simplex virus type 1. A novel target for anti-herpetic therapy.
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.
Amici
C
C
Department of Biology, University of Rome Tor Vergata, 00133 Rome, Italy.
Belardo
G
G
Rossi
A
A
Santoro
M G
MG
D000212:Acyclovir / Q000494:pharmacology; D000818:Animals; D000894:Anti-Inflammatory Agents, Non-Steroidal / Q000494:pharmacology*; D000998:Antiviral Agents / Q000494:pharmacology; D002522:Chlorocebus aethiops; D003513:Cycloheximide / Q000494:pharmacology; D003609:Dactinomycin / Q000494:pharmacology; D015195:Drug Design; D004789:Enzyme Activation; D004791:Enzyme Inhibitors / Q000494:pharmacology; D015966:Gene Expression Regulation, Fungal / Q000187:drug effects / Q000502:physiology*; D018259:Herpesvirus 1, Human / Q000187:drug effects / Q000235:genetics / Q000502:physiology*; D006801:Humans; D051550:I-kappa B Kinase; D007700:Kinetics; D007822:Laryngeal Neoplasms; D008715:Methionine / Q000378:metabolism; D016328:NF-kappa B / Q000378:metabolism*; D009447:Neuroblastoma; D011454:Prostaglandins A / Q000494:pharmacology; D017346:Protein Serine-Threonine Kinases / Q000378:metabolism*; D011994:Recombinant Proteins / Q000378:metabolism; D014162:Transfection; D014407:Tumor Cells, Cultured; D014709:Vero Cells; D014779:Virus Replication / Q000187:drug effects / Q000502:physiology*
D000894:Anti-Inflammatory Agents, Non-Steroidal; D000998:Antiviral Agents; D004791:Enzyme Inhibitors; D016328:NF-kappa B; D011454:Prostaglandins A; D011994:Recombinant Proteins; D003609:Dactinomycin; D003513:Cycloheximide; D008715:Methionine; D017346:Protein Serine-Threonine Kinases; C496559:CHUK protein, human; D051550:I-kappa B Kinase; C496560:IKBKB protein, human; C496565:IKBKE protein, human; C100573:prostaglandin A1; D000212:Acyclovir