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Virology. 2003 Mar 30;308(1):37-47.

Lethal mutagenesis of the prototypic arenavirus lymphocytic choriomeningitis virus (LCMV).

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Centro de Biologia Molecular Severo Ochoa (CSIC, UAM), Universidad Autonoma de Madrid, Cantoblanco, 28049 Madrid, Spain.


Passage of the prototypic arenavirus lymphocytic choriomenigitis virus (LCMV) in cultured cells in the presence of the mutagenic agent 5-fluorouracil (FU) resulted in efficient and systematic virus extinction under conditions that did not significantly affect cell survival. FU-mediated extinction of LCMV was associated with 3.6- to 10-fold increases in the mutation frequencies for the three viral genes examined, but with only very modest effects on virus replication and transcription during a single round of infection. Likewise, FU did not affect expression of a LCMV minigenome. In contrast, the well documented antiviral effect of ribavirin against LCMV was not associated with significant increases in virus mutation frequencies, but rather with a dramatic inhibition of both viral RNA synthesis and LCMV minigenome expression. Mutagen induced viral extinction has been recently reported for positive strand RNA viruses polio and foot-and-mouth disease, and the lentivirus HIV-1. Our findings indicate that lethal mutagenesis can be effective also against LCMV, a negative strand RNA virus. Moreover, FU treatment prevented the establishment of LCMV persistent infection in mice deficient in B and T cells, suggesting the feasibility in vivo of lethal mutagenesis as a novel antiviral strategy.

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