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Viruses 2012, 4(11), 2786-2805; doi:10.3390/v4112786

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

1,3,*  and 4,*
1 Centro de Biología Molecular “Severo Ochoa” (CSIC-UAM), Campus de Cantoblanco 28049, Madrid, Spain 2 Genética, Facultad de Ciencias, Campus de Teatinos, Universidad de Málaga, 29071, Málaga, Spain 3 Centro de Investigación Biomédica en Red de Enfermedades Hepáticas y Digestivas (CIBERehd), 08036 Barcelona, Spain 4 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 / Revised: 17 October 2012 / Accepted: 25 October 2012 / Published: 6 November 2012
(This article belongs to the Special Issue Arenaviruses)
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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 viral quasispecies; lymphocytic choriomeningitis virus; 5-fluorouracil; antiviral treatment
This is an open access article distributed under the Creative Commons Attribution License (CC BY) which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.

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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.

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