Ribavirin Can Be Mutagenic for Arenaviruses

Abstract

Arenaviruses include several important human pathogens, and there are very limited options of preventive or therapeutic interventions to combat these viruses. An off-label use of the purine nucleoside analogue ribavirin (1-␤-D-ribofuranosyl-1-H-1,2,4-triazole-3-carboxamide) is the only antiviral treatment currently available for arenavirus infections. However, the ribavirin antiviral mechanism action against arenaviruses remains unknown. Here we document that ribavirin is mutagenic for the prototypic arenavirus lymphocytic choriomeningitis virus (LCMV) in cell culture. The mutagenic activity of ribavirin on LCMV was observed under single-and multiple-passage regimes and could not be accounted for by a decrease of the intracellular GTP pool promoted by ribavirin-mediated inhibition of inosine monophosphate dehydrogenase (IMPDH). Our findings suggest that the antiviral activity of ribavirin on arenaviruses might be exerted, at least partially, by lethal mutagenesis. Implications for antiarenavirus therapy are discussed.

Inhibition of Arenavirus by A3, a Pyrimidine Biosynthesis Inhibitor

“…This observation suggests that in addition to its inhibitory effect on viral RNA synthesis, A3 could also exert a mutagenic effect on the viral genome RNA that would result in a decreased virus-specific infectivity, which would further contribute to the antiviral activity of A3. It should be noted that a precedent for this has been reported for ribavirin, a drug that, depending on the experimental conditions used, can both inhibit viral RNA synthesis and have a mutagenic effect on the arenavirus genome (28,52). However, based on its structure (Fig.…”

“…Ribavirin is known to affect the cellular GTP pool (51) and also to promote lethal mutagenesis (28), whereas A3 targets the pyrimidine biosynthesis pathway and thereby directly affects the UTP pools. Because different pathways appear to contribute to the antiarenaviral activities of A3 and ribavirin, we reasoned that ribavirin and A3 combination therapy might offer benefits over each single monotherapy.…”

“…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).…”

Diseases of the central nervous system caused by lymphocytic choriomeningitis virus and other arenaviruses

“…With regard to antiviral treatments, the nucleoside analogue ribavirin does have efficacy against multiple arenaviruses and has reduced mortality from LF virus when administered early in infection (Stephen et al, 1977;McCormick et al, 1986;Kilgore et al, 1997). It likely interferes with viral replication and may also induce mutations lethal to the virus (Moreno et al, 2011). However, its administration often leads to anemia and sometimes to other side-effects.…”

Lujo virus: current concepts

“…This has been demonstrated at subinhibitory concentrations of ribavirin. 30 This would suggest potential for combination or adjunctive therapies.…”