Arenaviruses and Lethal Mutagenesis. Prospects for New Ribavirin-based Interventions

Abstract

Lymphocytic choriomeningitis virus (LCMV) has contributed to unveil some of the molecular mechanisms of lethal mutagenesis, or loss of virus infectivity due to increased mutation rates. Here we review these developments, and provide additional evidence that ribavirin displays a dual mutagenic and inhibitory activity on LCMV that can be relevant to treatment designs. Using 5-fluorouracil as mutagenic agent and ribavirin either as inhibitor or mutagen, we document an advantage of a sequential inhibitor-mutagen administration over the corresponding combination treatment to achieve a low LCMV load in cell culture. This advantage is accentuated in the concentration range in which ribavirin acts mainly as an inhibitor, rather than as mutagen. This observation reinforces previous theoretical and experimental studies in supporting a sequential inhibitor-mutagen administration as a possible antiviral design. Given recent progress in the development of new inhibitors of arenavirus replication, our results suggest new options of ribavirin-based anti-arenavirus treatments.

Extinction of Hepatitis C Virus by Ribavirin in Hepatoma Cells Involves Lethal Mutagenesis

“…Significantly, extinction by the non-mutagenic mycophenolic acid did not alter the specific infectivity of HCV and, with our quantification procedures infectivity was still detectable when extracellular HCV RNA was not. This is in contrast to the decrease in specific infectivity associated with Rib-mediated extinction, a hallmark of lethal mutagenesis [35], [42], [57], [61], [62], [97], [113] (Fig. 7).…”

“…Recent studies of antiviral designs based on lethal mutagenesis render important a clarification of whether mutagenesis of the viral genome occurs in the course of an antiviral treatment. Indeed, a potential advantage of a sequential inhibitor-mutagen administration over the corresponding combination, necessitates that a mutagenic agent be part of the therapy [95]–[97]. We are currently extending to HCV our previous approach of testing the efficacy of alternative administration protocols [reviewed in [114]].…”

“…Recent model studies with different virus-host systems have indicated that when a mutagenic agent participates in therapy, a sequential administration of an inhibitor first, followed by a mutagenic agent may be more effective than the corresponding combination therapy to achieve virus extinction [49], [95]–[97]. The advantage of a sequential administration depends on the concentrations of mutagen and inhibitor used, and it requires that one of the drugs used for therapy acts as a mutagenic agent [95]–[97]. Thus, with the advent of DAAs, it is important to clarify the mechanism of Rib activity against HCV to compare the effectiveness of alternative antiviral protocols first in cell culture and then in animal models and clinical trials.…”

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.…”

Quasispecies and Drug Resistance

“…(Figure reproduced from Domingo et al (2012) with permission from ASM) mutants had to be competent in RNA replication to be inhibitory (Perales et al 2007). This requirement is one of the factors that contribute to an advantage of sequential inhibitor-mutagen treatment over the corresponding combination, to prevent the selection of inhibitor-escape mutants and favor virus extinction (Iranzo et al 2011;Moreno et al 2012;Perales et al 2009Perales et al , 2012.…”