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The clinically approved proteasome inhibitor PS-341 efficiently blocks influenza A virus and vesicular stomatitis virus propagation by establishing an antiviral state.
Dudek, Sabine Eva; Luig, Christina; Pauli, Eva-Katharina; Schubert, Ulrich; Ludwig, Stephan.
Afiliación
  • Dudek SE; Institute of Molecular Virology, Centre for Molecular Biology of Inflammation, Muenster, Germany.
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.
Asunto(s)

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

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