Pathways to extinction: beyond the error threshold

Abstract

Since the introduction of the quasispecies and the error catastrophe concepts for molecular evolution by Eigen and their subsequent application to viral populations, increased mutagenesis has become a common strategy to cause the extinction of viral infectivity. Nevertheless, the high complexity of virus populations has shown that viral extinction can occur through several other pathways apart from crossing an error threshold. Increases in the mutation rate enhance the appearance of defective forms and promote the selection of mechanisms that are able to counteract the accelerated appearance of mutations. Current models of viral evolution take into account more realistic scenarios that consider compensatory and lethal mutations, a highly redundant genotype-to-phenotype map, rough fitness landscapes relating phenotype and fitness, and where phenotype is described as a set of interdependent traits. Further, viral populations cannot be understood without specifying the characteristics of the environment where they evolve and adapt. Altogether, it turns out that the pathways through which viral quasispecies go extinct are multiple and diverse.

Tautomerism provides a molecular explanation for the mutagenic properties of the anti-HIV nucleoside 5-aza-5,6-dihydro-2′-deoxycytidine

“…Several antiviral agents are proposed to work at least in part by a chemical version of lethal mutagenesis [e.g., ribavirin against hepatitis C virus (18-22), 5-hydroxy-2′-deoxycytidine against HIV (7), and T-705 against influenza viruses (23)]. When a sufficient number of these mutagenic nucleoside analogs is incorporated into viral genomes, the analogs increase the viral mutation rate above the error catastrophe limit, the rate above which no viable progeny are produced (6,(24)(25)(26)(27). This work aimed to understand the molecular basis underlying the biological phenomenon of lethal mutagenesis induced by mutagenic nucleotides.…”

Tempo and mode of inhibitor–mutagen antiviral therapies: A multidisciplinary approach

“…Since the dawn of quasispecies theory (17), the use of mutagens has been proposed as a plausible strategy to induce viral extinction (18,19). A significant increase in the mutation rate has been, indeed, successful to cause the extinction of infectivity in many different viral systems (20,21), although the mechanisms through which extinction supervenes are diverse and related to a variety of molecular and population responses (22). In particular, increased mutagenesis can also bear beneficial effects for viral populations through an enhancement of their diversity, which promotes adaptation of low-fitness viruses (23) and facilitates the appearance of resistance mutants when an inhibitor of viral replication is present (24).…”

Getting to Know Viral Evolutionary Strategies: Towards the Next Generation of Quasispecies Models

“…In vitro experiments to test this so-called lethal mutagenesis hypothesis have achieved remarkable success (Agudo et al 2009;Crotty et al 2001;Dapp et al 2009;Grande-Pérez et al 2002;Holland et al 1990;Loeb et al 1999;Severson et al 2003;Sierra et al 2000), demonstrating that viral extinction can indeed be caused by sufficiently large increases in the mutation rate (reviewed in Perales et al 2011b;Domingo et al 2012). This success nonetheless, there is as yet no convincing proof that the observed extinctions are the consequence of crossing an informational error threshold of the kind described in Eigen's quasispecies theory (Bull et al 2007;Manrubia et al 2010; see also Chaps. 13 and 14).…”