BACKGROUND: Herpes simplex virus type 1 (HSV-1) is a potent inducer of nuclear factor-KB (NF-kappaB), a cellular transcription factor with a crucial role in promoting inflammation and controlling cell proliferation and survival. OBJECTIVES: On the basis of the recent demonstration that HSV-1-induced NF-kappaB is actively recruited to KB-binding sites in the HSV-1 infected-cell protein 0 (ICPO) promoter enhancing viral transcription and replication, we investigated the effect of proteasome inhibitors MG132, MG115 and epoxomicin, which block NF-kappaB function by preventing the degradation of the inhibitory proteins IkappaBalpha, on HSV-1-induced NF-kappaB activation and viral replication. METHODS: Antiviral activity of proteasome inhibitors was analysed in HSV-1-infected HEp2 cells by determining infective virus titres by CPE50%, viral RNA synthesis by RT-PCR, and viral protein synthesis by immunoblot analysis or immunofluorescence. ICPO transcription was studied in transient transfection experiments using the ICPO promoter-luciferase IE1-Luc construct. IkappaBalpha degradation and NF-kappaB activity were determined by immunoblot analysis and EMSA, respectively. RESULTS: Proteasome inhibitors were found to prevent HSV-1-induced NF-kappaB activation in the early phase of infection. Block of virus-induced NF-kappaB activation resulted in inhibiting HSV-1 ICPO gene expression, in decreasing the level of immediate-early and late viral proteins, and ultimately in greatly suppressing viral replication. The antiviral effect was lost if treatment was started after NF-kappaB activation, and appeared to be independent of the HSV-1-induced activation of the JNK pathway.CONCLUSIONS: Proteasome inhibitors possess NF-kappaB-dependent antiherpetic activity. The results described further identify the IKK/NF-kappaB pathway as a suitable target for novel antiherpetic drugs
La Frazia, S., Amici, C., & Santoro, M.G. (2006). Antiviral activity of proteasome inhibitors in herpes simplex virus-1 infection: role of nuclear factor-kappaB. ANTIVIRAL THERAPY, 11(8), 995-1004.
Tipologia: | Articolo su rivista |
Citazione: | La Frazia, S., Amici, C., & Santoro, M.G. (2006). Antiviral activity of proteasome inhibitors in herpes simplex virus-1 infection: role of nuclear factor-kappaB. ANTIVIRAL THERAPY, 11(8), 995-1004. |
URL: | http://www.intmedpress.com/serveFile.cfm?sUID=36cd9950-354c-4e68-b538-bb03248cda5f |
Lingua: | English |
Settore Scientifico Disciplinare: | Settore MED/07 - Microbiologia e Microbiologia Clinica |
Revisione (peer review): | Sì, ma tipo non specificato |
Tipo: | Articolo |
Rilevanza: | Rilevanza internazionale |
Stato di pubblicazione: | Pubblicato |
Data di pubblicazione: | 2006 |
Titolo: | Antiviral activity of proteasome inhibitors in herpes simplex virus-1 infection: role of nuclear factor-kappaB |
Autori: | |
Autori: | La Frazia, S; Amici, C; Santoro, MG |
Appare nelle tipologie: | 01 - Articolo su rivista |