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Journal of Virology, August 2005, p. 10451-10459, Vol. 79, No. 16
0022-538X/05/$08.00+0     doi:10.1128/JVI.79.16.10451-10459.2005
Copyright © 2005, American Society for Microbiology. All Rights Reserved.

Mutagenesis-Induced, Large Fitness Variations with an Invariant Arenavirus Consensus Genomic Nucleotide Sequence

Ana Grande-Pérez,^1, Gema Gómez-Mariano,¹ Pedro R. Lowenstein,² and Esteban Domingo^1*

Centro de Biología Molecular "Severo Ochoa" (CSIC-UAM), Cantoblanco, E-28049 Madrid, Spain,¹ Department of Medicine, Department of Molecular and Medical Pharmacology, and Gene Therapeutics Research Institute, Cedars-Sinai Medical Center, and Department of Medicine, University of California, Los Angeles, California²

Received 28 February 2005/ Accepted 9 May 2005

Enhanced mutagenesis may result in RNA virus extinction, but the molecular events underlying this process are not well understood. Here we show that 5-fluorouracil (FU)-induced mutagenesis of the arenavirus lymphocytic choriomeningitis virus (LCMV) resulted in preextinction populations whose consensus genomic nucleotide sequence remained unaltered. Furthermore, fitness recovery passages in the absence of FU, or alternate virus passages in the presence and absence of FU, led to profound differences in the capacity of LCMV to produce progeny, without modification of the consensus genomic sequence. Molecular genetic analysis failed to produce evidence of hypermutated LCMV genomes. The results suggest that low-level mutagenesis to enrich the viral population with defector, interfering genomes harboring limited numbers of mutations may mediate the loss of infectivity that accompanies viral extinction.

Present address: Departamento de Genética, Universidad de Málaga, 29071 Málaga, Spain.

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