Development of a new Tacaribearenavirus infection model and its use to explore antiviral activity of a novelaristeromycin analog

Authors

Brian B. Gowen, Utah State UniversityFollow
M. H. Wong
D. Larson
W. Ye
K. H. Jung, Utah State UniversityFollow
E. J. Sefing
Ramona T. Skirpstunas, Utah State UniversityFollow
Donald F. Smee, Utah State UniversityFollow
John D. Morrey, Utah State UniversityFollow
S. W. Schneller

Document Type

Article

Journal/Book Title/Conference

PLoS ONE

Volume

5

Publication Date

2010

Creative Commons License

This work is licensed under a Creative Commons Attribution 3.0 License.

Abstract

Background

A growing number of arenaviruses can cause a devastating viral hemorrhagic fever (VHF) syndrome. They pose a public health threat as emerging viruses and because of their potential use as bioterror agents. All of the highly pathogenic New World arenaviruses (NWA) phylogenetically segregate into clade B and require maximum biosafety containment facilities for their study. Tacaribe virus (TCRV) is a nonpathogenic member of clade B that is closely related to the VHF arenaviruses at the amino acid level. Despite this relatedness, TCRV lacks the ability to antagonize the host interferon (IFN) response, which likely contributes to its inability to cause disease in animals other than newborn mice.

Methodology/Principal Findings

Here we describe a new mouse model based on TCRV challenge of AG129 IFN-α/β and -γ receptor-deficient mice. Titration of the virus by intraperitoneal (i.p.) challenge of AG129 mice resulted in an LD₅₀ of ∼100 fifty percent cell culture infectious doses. Virus replication was evident in the serum, liver, lung, spleen, and brain 4–8 days after inoculation. MY-24, an aristeromycin derivative active against TCRV in cell culture at 0.9 µM, administered i.p. once daily for 7 days, offered highly significant (P

Conclusions/Significance

MY-24 is believed to act as an inhibitor of S-adenosyl-L-homocysteine hydrolase, but our findings suggest that it may ameliorate disease by blunting the effects of the host response that play a role in disease pathogenesis. The new AG129 mouse TCRV infection model provides a safe and cost-effective means to conduct early-stage pre-clinical evaluations of candidate antiviral therapies that target clade B arenaviruses.

Comments

PLoS ONE (2010) 5, pii: e12760

Recommended Citation

Gowen, B.B., Wong, M.H., Larson, D., Ye, W., Jung, K.H., Sefing, E.J., Skirpstunas, R., Smee, D.F., Morrey, J.D. and Schneller, S.W. Development of a new Tacaribe arenavirus infection model and its use to explore antiviral activity of a novel aristeromycin analog. PLoS ONE (2010) 5, pii: e12760.