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Arenaviruses and Lethal Mutagenesis. Prospects for New Ribavirin-based Interventions
Centro de Biología Molecular “Severo Ochoa” (CSIC-UAM), Campus de Cantoblanco 28049, Madrid, Spain
Genética, Facultad de Ciencias, Campus de Teatinos, Universidad de Málaga, 29071, Málaga, Spain
Centro de Investigación Biomédica en Red de Enfermedades Hepáticas y Digestivas (CIBERehd), 08036 Barcelona, Spain
Centro de Investigación en Sanidad Animal (CISA), Carretera de Algete a El Casar s/n, 28130 Valdeolmos, Madrid, Spain
* Authors to whom correspondence should be addressed.
Received: 11 October 2012; in revised form: 17 October 2012 / Accepted: 25 October 2012 / Published: 6 November 2012
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.
Keywords: viral quasispecies; lymphocytic choriomeningitis virus; 5-fluorouracil; antiviral treatment
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Moreno, H.; Grande-Pérez, A.; Domingo, E.; Martín, V. Arenaviruses and Lethal Mutagenesis. Prospects for New Ribavirin-based Interventions. Viruses 2012, 4, 2786-2805.
Moreno H, Grande-Pérez A, Domingo E, Martín V. Arenaviruses and Lethal Mutagenesis. Prospects for New Ribavirin-based Interventions. Viruses. 2012; 4(11):2786-2805.
Moreno, Héctor; Grande-Pérez, Ana; Domingo, Esteban; Martín, Verónica. 2012. "Arenaviruses and Lethal Mutagenesis. Prospects for New Ribavirin-based Interventions." Viruses 4, no. 11: 2786-2805.