The clinically approved proteasome inhibitor PS-341 efficiently blocks influenza A virus and vesicular stomatitis virus propagation by establishing an antiviral state.
J Virol
; 84(18): 9439-51, 2010 Sep.
Article
en En
| MEDLINE
| ID: mdl-20592098
Recently it has been shown that the proinflammatory NF-kappaB pathway promotes efficient influenza virus propagation. Based on these findings, it was suggested that NF-kappaB blockade may be a promising approach for antiviral intervention. The classical virus-induced activation of the NF-kappaB pathway requires proteasomal degradation of the inhibitor of NF-kappaB, IkappaB. Therefore, we hypothesized that inhibition of proteasomal IkappaB degradation should impair influenza A virus (IAV) replication. We chose the specific proteasome inhibitor PS-341, which is a clinically approved anticancer drug also known as Bortezomib or Velcade. As expected, PS-341 treatment of infected A549 cells in a concentration range that was not toxic resulted in a significant reduction of progeny virus titers. However, we could not observe the proposed suppression of NF-kappaB-signaling in vitro. Rather, PS-341 treatment resulted in an induction of IkappaB degradation and activation of NF-kappaB as well as the JNK/AP-1 pathway. This coincides with enhanced expression of antiviral genes, such as interleukin-6 and, most importantly, MxA, which is a strong interferon (IFN)-induced suppressor of influenza virus replication. This suggests that PS-341 may act as an antiviral agent via induction of the type I IFN response. Accordingly, PS-341 did not affect virus titers in Vero cells, which lack type I IFN genes, but strongly inhibited replication of vesicular stomatitis virus (VSV), a highly IFN-sensitive pathogen. Thus, we conclude that PS-341 blocks IAV and VSV replication by inducing an antiviral state mediated by the NF-kappaB-dependent expression of antivirus-acting gene products.
Texto completo:
1
Colección:
01-internacional
Base de datos:
MEDLINE
Asunto principal:
Antivirales
/
Virus de la Influenza A
/
Pirazinas
/
Ácidos Borónicos
/
Vesiculovirus
Límite:
Humans
Idioma:
En
Revista:
J Virol
Año:
2010
Tipo del documento:
Article
País de afiliación:
Alemania
Pais de publicación:
Estados Unidos