Development of a new tacaribe arenavirus infection model and its use to explore antiviral activity of a novel aristeromycin analog.
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.


RESULTS
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 LD(50) 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<0.001) protection against mortality in the AG129 mouse TCRV infection model, without appreciably reducing viral burden. In contrast, in a hamster model of arenaviral hemorrhagic fever based on challenge with clade A Pichinde arenavirus, MY-24 did not offer significant protection against mortality.


CONCLUSIONS
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.
Gowen
Brian B
BB
Department of Animal, Dairy, and Veterinary Sciences, Institute for Antiviral Research, Utah State University, Logan, Utah, USA. brian.gowen@usu.edu
Wong
Min-Hui
MH
Larson
Deanna
D
Ye
Wei
W
Jung
Kie-Hoon
KH
Sefing
Eric J
EJ
Skirpstunas
Ramona
R
Smee
Donald F
DF
Morrey
John D
JD
Schneller
Stewart W
SW
D000241:Adenosine / Q000008:administration & dosage / Q000031:analogs & derivatives* / Q000737:chemistry; D000818:Animals; D000998:Antiviral Agents / Q000008:administration & dosage* / Q000737:chemistry; D001117:Arenaviridae Infections / Q000188:drug therapy* / Q000401:mortality / Q000821:virology; D006477:Arenaviruses, New World / Q000187:drug effects / Q000502:physiology*; D002522:Chlorocebus aethiops; D006224:Cricetinae; D004195:Disease Models, Animal; D005260:Female; D006801:Humans; D008297:Male; D008647:Mesocricetus; D051379:Mice; D018345:Mice, Knockout; D014709:Vero Cells; D014779:Virus Replication
D000998:Antiviral Agents; C030034:aristeromycin; D000241:Adenosine