Viral quasispecies

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Originally used to model the evolution of the first macromolecules on earth , the quasispecies concept has been applied to populations of a virus within its host [1]. The quasispecies model is deemed to be relevant to RNA viruses because they have high mutation rates in the order of one per round of replication [2], and viral populations, while not infinite, are extremely large. Thus the practical conditions for quasispecies formation are thought to exist.

The significance of the quasispecies model for virology is that, if the mutation rate is sufficiently high, selection acts on clouds of mutants rather than individual sequences [3]. Therefore, the evolutionary trajectory of the viral infection cannot be predicted solely from the characteristics of the fittest sequence.

The importance of quasispecies concepts in virology has been the subject of some discussion [4][5]. Significantly, it has been shown that there is no necessary conflict between a quasispecies model of intra-host evolution and traditional population genetics [3]. Instead, viral quasispecies can be considered as cases of coupled mutation-selection balance models for haploid organisms.

It may be useful to understand the etymology of the term. Quasispecies are clouds of related elements that behave almost (quasi) like a single type of molecule (species). There is no suggestion that a viral quasispecies resembles a traditional biological species.

1 Possible consequences for viral evolution
2 References
3 See also

[edit] Possible consequences for viral evolution

fig. 1: A sharp selection profile.

fig. 2: A broader, more realistic selection profile.

[edit] Error Threshold.

This may be defined as “The inability of a genetic element to be maintained in a population as the fidelity of its replication machinery decreases beyond a certain threshold value” [6].

In theory, if the mutation rate was sufficiently high, the viral population would not be able to maintain the genotype with the highest fitness, and therefore the ability of the population to adapt to its environment would be compromised. A practical application of this dynamic is in antiviral drugs employing lethal mutagenesis. For example, increased doses of the mutagen Ribavirin reduces the infectivity of Poliovirus [7].

However, these models assume that only the mutations that occur in the fittest sequence are deleterious, and furthermore that they are non-lethal (fig. 1). It has been argued that, if we take into account the deleterious effect of mutations on the population of variants and the fact that that many mutations are lethal (fig. 2), then the Error Threshold disappears, i.e. the fittest sequence always maintains itself [3] [6] [8]. Empirical data on the effect of mutations in viruses is rare, but appears to correspond more closely to fig. 2 [9].

[edit] Mutational Robustness.

The long-term evolution of the virus may be influenced in that it may be a better ESS (Evolutionarily Stable Strategy) to generate a broad quasispecies with members of approximately equal fitness than to have a sharply defined 'most fit' single genotype (with mutational neighbours substantially less fit). This has been called 'survival of the flattest' - referring to the fitness profiles of the two strategies respectively [10].

Over the long-term, a flatter fitness profile might better allow a quasispecies to exploit changes in selection pressure, analogous to the way sexual organisms use recombination to preserve diversity in a population. At least in simulations, a slower replicator can be shown to be able to outcompete a faster one in cases where it is more robust and the mutation rate is high [11].

[edit] Cooperation.

Experimental manipulation of Poliovirus to give them a higher-fidelity polymerase – and hence reduce their mutation rate – showed these variants to have lower pathogenicity than wild-type sequences [12]. Pathogenicity could then be restored by mutagen application. This was interpreted to mean lower mutation rates had reduced the adaptability (or breadth) of the quasispecies. The mutant viruses extracted from brain tissue were not themselves pathogenic, and the authors speculate that there may be complementation between variant members of the quasispecies that could enable viruses to colonize different host tissues and systems.

[edit] References

1. Novak, M.A. (1992). Trends Ecol. Evol. 7:118-121
2. Drake, J.W. & Holland, J.J. (1999). Proc. Natl Acad. Sci. USA. 96:13910-3.
3. Wilke, C. (2005). BMC Evol. Biol. 5:44
4. Holmes, E.C. & Moya, A. (2002). J Virol 76:460-462.
5. Domingo, E. (2002). J. Virol. 76:463-465.
6. Summers J. & Litwin, S. (2006). J. Virol. 80:20-26
7. Crotty, S. et al. (2001) Proc. Natl Acad. Sci. USA. 98:6895-6900
8. Wagner G.P. & Krall, P. (1993) J. Math. Biol. 32:33–44.
9. Sanjuan et al. (2004) Proc. Natl Acad. Sci. USA. 101:8396-8401
10. Wilke et al. (2001). Nature 412:331-333.
11. Nimwegen, E. et al. (1999). Proc. Natl Aca.d Sci. USA. 96:9716-9720
12. Vignuzzi, M. et al. (2006) Nature 439:344-348