The Clinically Approved Proteasome Inhibitor PS-341 Efficiently Blocks Influenza A Virus and Vesicular Stomatitis Virus Propagation by Establishing an Antiviral State

Recently it has been shown that the proinflammatory NF-kappa B pathway promotes efficient influenza virus propagation. Based on these findings, it was suggested that NF-kappa B blockade may be a promising approach for antiviral intervention. The classical virus-induced activation of the NF-kappa B pathway requires proteasomal degradation of the inhibitor of NF-kappa B, I kappa B. Therefore, we hypothesized that inhibition of proteasomal I kappa B 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-kappa B-signaling in vitro. Rather, PS-341 treatment resulted in an induction of I kappa B degradation and activation of NF-kappa B 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-kappa B-dependent expression of antivirus-acting gene products.