Enhancement of the infectivity of SARS-CoV in BALB/c mice by IMP dehydrogenase inhibitors, including ribavirin.
Because of the conflicting data concerning the SARS-CoV inhibitory efficacy of ribavirin, an inosine monophosphate (IMP) dehydrogenase inhibitor, studies were done to evaluate the efficacy of ribavirin and other IMP dehydrogenase inhibitors (5-ethynyl-1-beta-D-ribofuranosylimidazole-4-carboxamide (EICAR), mizoribine, and mycophenolic acid) in preventing viral replication in the lungs of BALB/c mice, a replication model for severe acute respiratory syndrome (SARS) infections (Subbarao, K., McAuliffe, J., Vogel, L., Fahle, G., Fischer, S., Tatti, K., Packard, M., Shieh, W.J., Zaki, S., Murphy, B., 2004. Prior infection and passive transfer of neutralizing antibody prevent replication of severe acute respiratory syndrome coronavirus (SARS-CoV) in the respiratory tract of mice. J. Virol. 78, 3572-3577). Ribavirin given at 75 mg/kg 4 h prior to virus exposure and then given twice daily for 3 days beginning at day 0 was found to increase virus lung titers and extend the length of time that virus could be detected in the lungs of mice. Other IMP dehydrogenase inhibitors administered near maximum tolerated doses using the same dosing regimen as for ribavirin were found to slightly enhance virus replication in the lungs. In addition, ribavirin treatment seemed also to promote the production of pro-inflammatory cytokines 4 days after cessation of treatment, although after 3 days of treatment ribavirin inhibited pro-inflammatory cytokine production in infected mice, significantly reducing the levels of the cytokines IL-1alpha, interleukin-5 (IL-5), monocyte chemotactic protein-1 (MCP-1), and granulocyte-macrophage colony stimulating factor (GM-CSF). These findings suggest that ribavirin may actually contribute to the pathogenesis of SARS-CoV by prolonging and/or enhancing viral replication in the lungs. By not inhibiting viral replication in the lungs of infected mice, ribavirin treatment may have provided a continual source of stimulation for the inflammatory response thought to contribute to the pathogenesis of the infection. Our data do not support the use of ribavirin or other IMP dehydrogenase inhibitors for treating SARS infections in humans.
Barnard
Dale L
DL
Institute for Antiviral Research, Utah State University, Logan, 84322-5600, USA. honery@usu.edu
Day
Craig W
CW
Bailey
Kevin
K
Heiner
Matthew
M
Montgomery
Robert
R
Lauridsen
Larry
L
Winslow
Scott
S
Hoopes
Justin
J
Li
Joseph K-K
JK
Lee
Jongdae
J
Carson
Dennis A
DA
Cottam
Howard B
HB
Sidwell
Robert W
RW
D000818:Animals; D000998:Antiviral Agents / Q000494:pharmacology*; D018938:Caco-2 Cells; D002470:Cell Survival / Q000187:drug effects; D002522:Chlorocebus aethiops; D016207:Cytokines / Q000378:metabolism; D003588:Cytopathogenic Effect, Viral / Q000187:drug effects; D005260:Female; D006801:Humans; D007168:IMP Dehydrogenase / Q000037:antagonists & inhibitors*; D008168:Lung / Q000473:pathology / Q000821:virology; D051379:Mice; D008807:Mice, Inbred BALB C; D009173:Mycophenolic Acid / Q000494:pharmacology; D020411:Oligonucleotide Array Sequence Analysis; D012254:Ribavirin / Q000494:pharmacology*; D012263:Ribonucleosides / Q000494:pharmacology; D045473:Severe acute respiratory syndrome-related coronavirus / Q000187:drug effects / Q000201:enzymology / Q000472:pathogenicity / Q000502:physiology*; D045169:Severe Acute Respiratory Syndrome / Q000188:drug therapy* / Q000821:virology*; D013047:Specific Pathogen-Free Organisms; D014709:Vero Cells; D014779:Virus Replication / Q000187:drug effects*
D000998:Antiviral Agents; D016207:Cytokines; D012263:Ribonucleosides; C059077:5-ethynyl-1-ribofuranosylimidazole-4-carboxamide; D012254:Ribavirin; C010052:mizoribine; D007168:IMP Dehydrogenase; D009173:Mycophenolic Acid