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.
Highlights
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
Mutation frequencies are in agreement with values of Shannon entropy, a measure of the proportion of different sequences in a genome distribution. Both parameters are used to quantify the complexity of mutant spectra, which is influenced by the number of passages from a clonal origin, the multiplicity of infection (MOI), and the viral gene analyzed
Current research involves the use of mutagenic base or nucleoside analogues which are converted intracellularly in the nucleoside-triphosphate derivatives which are incorporated into viral RNA during elongation
Summary
Despite promising developments [9,10,11,12], no licensed vaccines are generally available, and current therapy is essentially limited to an off-label use of the antiviral agent ribavirin (1-β-D-ribofuranosyl-1H-1,2,4-triazole-3-carboxamide) (Rib) [13,14] This is why arenavirus-related diseases are an interesting target to explore new antiviral designs. Mutation frequencies are in agreement with values of Shannon entropy, a measure of the proportion of different sequences in a genome distribution Both parameters are used to quantify the complexity of mutant spectra, which is influenced by the number of passages from a clonal origin (i.e. starting with a plaque-purified virus), the multiplicity of infection (MOI), and the viral gene analyzed. Several studies indicate that the complexities of mutant spectra of LCMV are comparable to those determined for other RNA viruses [15]
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