Replication at Periodically Changing Multiplicity of Infection Promotes Stable Coexistence of Competing Viral Populations

Abstract

RNA viruses are widely used to study evolution experimentally. Many standard protocols of virus propagation and competition are done at nominally low multiplicity of infection (m.o.i.), but lead during one passage to two or more rounds of infection, of which the later ones are at high m.o.i. Here, we develop a model of the competition between wild type (wt) and a mutant under a regime of alternating m.o.i. We assume that the mutant is deleterious when it infects cells on its own, but derives a selective advantage when rare and coinfecting with wt, because it can profit from superior protein products created by the wt. We find that, under these assumptions, replication at alternating low and high m.o.i. may lead to the stable coexistence of wt and mutant for a wide range of parameter settings. The predictions of our model are consistent with earlier observations of frequency-dependent selection in vesicular stomatitis virus and human immunodeficiency virus type 1. Our results suggest that frequency-dependent selection may be common in typical evolution experiments with viruses.

Darwinian Principles Acting on Highly Mutable Viruses

“…In contrast to suppression or interference, components of mutant spectra can complement each other, thereby producing ensembles that show higher fitness than many of its individual components (Domingo et al, 1978;Duarte et al, 1994;Moreno et al, 1997;Novella, 2003;Wilke et al, 2004;Perales et al, 2007) (Figure 3.10). Among other examples in cell culture and in vivo, it is worth underlining the case of a marked, non-neurotropic poliovirus mutant that could not make its way into the brain of mice when inoculated alone, but reached the brain when coinoculated with neuropathogenic poliovirus populations (Vignuzzi et al, 2006) (discussed in Chapter 2 regarding PV fidelity mutants).…”

Viral Fitness as a Measure of Adaptation

“…Furthermore, intracellular competition may involve complementation or interference between the mutant clouds originated by the two viruses (Novella, 2003;García-Arriaza et al, 2004;Wilke et al, 2004;Domingo, 2006;Perales et al, 2010) The situation can become even more complex in the case in which the yield of one virus is higher than the other as a result of the first infection wave, and if the extent of intracellular competition in the second infection wave affects the relative replication capacity of the two viruses.…”

“…Viral vectors and subgenomic replicon constructs can be designed to limit replication to a single cycle, avoiding subsequent, second wave cell infections [as examples, see (Mansky, 1998;Scholle et al, 2004)]. This and other alternatives pose technical difficulties that have been previously discussed (Wilke et al, 2004;Domingo, 2006;Wargo and Kurath, 2012). The virus titer at a defined time (or at multiple times) postinfection can be used as a surrogate fitness value, avoiding intracellular competition between the viruses under comparison.…”

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

“…The combination of theory and experiment led to the proposal of the lethal defection model, according to which defectors play an important role in virus extinction. The term defector had been previously used to refer to other types of non-functional genomes in models of RNA virus evolution [78,79]. In lethal mutagenesis, a defector is a genome that manifests some defect during its replication cycle, that may or may not complete production of infectious particles, but that is competent in RNA replication.…”