Population dynamics of RNA viruses: the essential contribution of mutant spectra.

Cells and their viral and cellular parasites are genetically highly diverse, and their genomes contain signs of past and present variation and mobility. The great adaptive potential of viruses, conferred on them by high mutation rates and quasispecies dynamics, demands new strategies for viral disease prevention and control. This necessitates a more detailed knowledge of viral population structure and dynamics. Here we review studies with the important animal pathogen Foot-and-mouth disease virus (FMDV) that document modulating effects of the mutant spectra that compose viral populations. As a consequence of interactions within mutant spectra, enhanced mutagenesis may lead to viral extinction, and this is currently investigated as a new antiviral strategy, termed virus entry into error catastrophe.

Foot-and-mouth disease virus evolution: exploring pathways towards virus extinction.

Foot-and-mouth disease virus (FMDV) is genetically and phenotypically variable. As a typical RNA virus, FMDV follows a quasispecies dynamics, with the many biological implications of such a dynamics. Mutant spectra provide a reservoir of FMDV variants, and minority subpopulations may become dominant in response to environmental demands or as a result of statistical fluctuations in population size. Accumulation of mutations in the FMDV genome occurs upon subjecting viral populations to repeated bottleneck events and upon viral replication in the presence of mutagenic base or nucleoside analogs. During serial bottleneck passages, FMDV survive during extended rounds of replication maintaining low average relative fitness, despite linear accumulation of mutations in the consensus genomic sequence. The critical event is the occurrence of a low frequency of compensatory mutations. In contrast, upon replication in the presence of mutagens, the complexity of mutant spectra increases, apparently no compensatory mutations can express their fitness-enhancing potential, and the virus can cross an error threshold for maintenance of genetic information, resulting in virus extinction. Low relative fitness and low viral load favor FMDV extinction in cell culture. The comparison of the molecular basis of resistance to extinction upon bottleneck passage and extinction by enhanced mutagenesis is providing new insights in the understanding of quasispecies dynamics. Such a comparison is contributing to the development of new antiviral strategies based on the transition of viral replication into error catastrophe.

Virus population dynamics, fitness variations and the control of viral disease: an update.

Viral quasispecies dynamics and variations of viral fitness are reviewed in connection with viral disease control. Emphasis is put on resistance of human immunodeficiency virus and some human DNA viruses to antiviral inhibitors. Future trends in multiple target antiviral therapy and new approaches based on virus entry into error catastrophe (extinction mutagenesis) are discussed.

Efficient virus extinction by combinations of a mutagen and antiviral inhibitors.

The effect of combinations of the mutagenic base analog 5-fluorouracil (FU) and the antiviral inhibitors guanidine hydrochloride (G) and heparin (H) on the infectivity of foot-and-mouth disease virus (FMDV) in cell culture has been investigated. Related FMDV clones differing up to 10(6)-fold in relative fitness in BHK-21 cells have been compared. Systematic extinction of intermediate fitness virus was attained with a combination of FU and G but not with the mutagen or the inhibitor alone. Systematic extinction of high-fitness FMDV required the combination of FU, G, and H. FMDV showing high relative fitness in BHK-21 cells but decreased replicative ability in CHO cells behaved as a low-fitness virus with regard to extinction mutagenesis in CHO cells. This confirms that relative fitness, rather than a specific genomic sequence, determines the FMDV response to enhanced mutagenesis. Mutant spectrum analysis of several genomic regions from a preextinction population showed a statistically significant increase in the number of mutations compared with virus passaged in parallel in the absence of FU and inhibitors. Also, in a preextinction population the types of mutations that can be attributed to the mutagenic action of FU were significantly more frequent than other mutation types. The results suggest that combinations of mutagenic agents and antiviral inhibitors can effectively drive high-fitness virus into extinction.