NOTES The Proteasome Inhibitor Velcade Enhances rather than Reduces Disease in Mouse Hepatitis Coronavirus-Infected Mice

Many viruses, including coronaviruses (CoVs), depend on a functional cellular proteasome for efficient infection in vitro. Hence, the proteasome inhibitor Velcade (bortezomib), a clinically approved anticancer drug, shown in an accompanying study (M. Raaben et al., J. Virol. 84:7869–7879, 2010) to strongly inhibit mouse hepatitis CoV (MHV) infection in cultured cells, seemed an attractive candidate for testing its antiviral properties in vivo. Surprisingly, however, the drug did not reduce replication of the virus in mice. Rather, inhibition of the proteasome caused enhanced infection with lethal outcome, calling for caution when using this type of drug during infection. The cellular proteasome is a central actor in protein degra-dation in eukaryotes (48). This barrel-shaped cytosolic com-plex has at least three peptidase activities (i.e., caspaselike, trypsinlike, and chymotrypsinlike activities), which are medi-ated by different subunits (11, 14, 15). Proteasomal degrada-tion is an important mechanism to control protein homeosta-sis, thereby regulating various basic cellular processes, including cell cycle regulation, cell adhesion, gene transcrip-tion, and apoptosis (12, 19, 28, 29, 37). Because proteasome inhibitors induce apoptosis preferen-tially in tumor cells, they represent a novel class of drugs in anticancer therapy (10, 16, 30, 42). One of these drugs, Vel