Development of a New Tacaribe Arenavirus Infection Model and Its Use to Explore Antiviral Activity of a Novel Aristeromycin Analog

Abstract

BackgroundA 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 FindingsHere 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<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/SignificanceMY-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.

Efficacy of the broad-spectrum antiviral compound BCX4430 against Zika virus in cell culture and in a mouse model

“…Wild-type mice typically do not display morbidity or mortality when infected peripherally with ZIKV. For this reason, we selected AG129 mice, which lack type I and type II IFN receptors, due to the susceptible nature of this mouse strain to various viruses (Gowen et al, 2010; Johnson and Roehrig, 1999; Partidos et al, 2011; Thibodeaux et al, 2012). …”

Inhibition of Arenavirus by A3, a Pyrimidine Biosynthesis Inhibitor

“…Notably, the antiviral and mutagenic activities of ribavirin could not be accounted for solely by depletion of intracellular GTP levels, which are a consequence of IMPDH inhibition (24)(25)(26)(27)(28). Several other compounds, including cytidine analogs that target cytosine triphosphate synthetase (29), analogs of adenosine that target S-adenosylhomocysteine hydrolase and interfere with the 5= cap of mRNA (30), and carbanucleoside analogs that target orotidylic acid decarboxylase (OMPD) and inhibit the conversion of OMP to UMP (31), have been shown to have antiarenaviral activities but did not exhibit advantages over ribavirin (25). Recently, a screen for inhibitors of influenza virus replication in cultured cells identified the de novo pyrimidine biosynthesis inhibitor compound A3 (32), which was found to have a broad inhibitory effect on multiplication of several other RNA viruses, including Newcastle disease virus, vesicular stomatitis virus, Sindbis virus, hepatitis C virus, West Nile virus, and dengue virus (32).…”

Progress in the Experimental Therapy of Severe ArenaViral Infections

“…However, although the Machupo, Junín, and Lassa models will be useful, they are restricted by the requirement for BSL-4 containment, which is available in only a handful of laboratories. A more accessible model that can be worked with at BSL-2 is based on infection of AG129 mice with Tacaribe virus (TCRV) [25]. TCRV is closely related to JUNV and the other South American HF arenaviruses, and has been used to evaluate a novel therapeutic agent [25].…”

“…A more accessible model that can be worked with at BSL-2 is based on infection of AG129 mice with Tacaribe virus (TCRV) [25]. TCRV is closely related to JUNV and the other South American HF arenaviruses, and has been used to evaluate a novel therapeutic agent [25]. …”

“…MY-24 (Fig 1F), an aristeromycin derivative believed to have activity as an inhibitor of S-adenosyl-L-homocysteine hydrolase, was found to have modest in vitro activity against TCRV, PICV and the Candid #1 strain of JUNV, prompting a series of in vivo studies in mice and hamsters [25]. Treatment consistently prevented death in mice challenged with TCRV, without reducing peak levels of virus in plasma or tissues.…”