2010 The Proteasome Inhibitor Velcade Enhances rather than Reduces Disease in Mouse Hepatitis Coronavirus-Infected Mice

6 Pages·2010·2.09 MB·English

JOURNAL OF VIROLOGY, Aug. 2010, p. 7880–7885
Vol. 84, No. 15
0022-538X/10/$12.00
doi:10.1128/JVI.00486-10
Copyright © 2010, American Society for Microbiology. All Rights Reserved.

NOTES

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

Matthijs Raaben,1† Guy C. M. Grinwis,2 Peter J. M. Rottier,1 and Cornelis A. M. de Haan1*

Virology Division, Department of Infectious Diseases and Immunology, Faculty of Veterinary Medicine, Utrecht University, Utrecht,
Netherlands,1 and Pathology Division, Department of Pathobiology, Utrecht University, Utrecht, Netherlands2

Received 4 March 2010/Accepted 7 May 2010

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-
cade (Bortezomib; formerly known as PS-341, LDP-341, and
MLM341), selectively blocks the chymotrypsinlike activity of
the catalytic core of the proteasome 20S subunit (1, 2). Vel-
cade has been clinically approved for the treatment of multiple
myelomas and mantle cell lymphoma (17, 18), while it also
displays anticancer activity against a range of different human
malignancies in cell culture and in animal models, including
myeloma, pancreatic cancer, lung cancer, prostate cancer,
chronic lymphocytic leukemia, and colon cancer (7, 31–33,
40, 41).
Viruses are obligatory intracellular parasites that exploit the
host cell for generating their progeny virions. A functional
cellular proteasomal system has been shown to be critical for
many viruses, including coronaviruses (CoVs), at different
stages of their life cycle (8, 20, 23, 24, 39, 43, 50). Thus, in

addition to their potential as anticancer drugs, proteasome
inhibitors also appear to be promising antiviral agents (39, 45).
Supporting this idea, proteasome inhibitors have been shown
to protect against coxsackievirus-induced myocarditis and to
prolong the survival of mice inoculated with Epstein-Barr vi-
rus-transformed B cells (13, 51). However, proteasome inhib-
itors have also been shown to exhibit immunosuppressive prop-
erties. They can, for example, alter TLR4-induced dendritic
cell activation and interfere with the immunological functions
of T cells (4, 27). Furthermore, cancer patients treated with
Velcade demonstrate increased reactivation of varicella herpes

* Corresponding author. Mailing address: Virology Division, De-
partment of Infectious Diseases and Immunology, Faculty of Veteri-
nary Medicine, Utrecht University, Yalelaan 1, 3584 CL Utrecht,
Netherlands. Phone: [phone]. Fax: [phone]. E-mail: c.a