title: 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.
authors.affiliation: Centro de Biología Molecular Severo Ochoa, Campus de Cantoblanco 28049, Madrid, Spain. hmoreno@cbm.uam.es
authors.forename: Héctor
authors.initials: H
authors.lastname: Moreno
authors.forename: Ana
authors.initials: A
authors.lastname: Grande-Pérez
authors.forename: Esteban
authors.initials: E
authors.lastname: Domingo
authors.forename: Verónica
authors.initials: V
authors.lastname: Martín
mesh_terms: D000818:Animals; D000998:Antiviral Agents / Q000494:pharmacology / Q000627:therapeutic use*; D001117:Arenaviridae Infections / Q000188:drug therapy*; D018050:Arenavirus / Q000187:drug effects / Q000235:genetics*; D004359:Drug Therapy, Combination; D005804:Genes, Lethal; D005814:Genes, Viral; D006801:Humans; D008217:Lymphocytic choriomeningitis virus / Q000187:drug effects / Q000235:genetics; D016296:Mutagenesis; D009154:Mutation; D012254:Ribavirin / Q000494:pharmacology / Q000627:therapeutic use*
chemical_list: D000998:Antiviral Agents; D012254:Ribavirin