Suppression of viral infectivity through lethal defection

Abstract

RNA viruses replicate with a very high error rate and give rise to heterogeneous, highly plastic populations able to adapt very rapidly to changing environments. Viral diseases are thus difficult to control because of the appearance of drug-resistant mutants, and it becomes essential to seek mechanisms able to force the extinction of the quasispecies before adaptation emerges. An alternative to the use of conventional drugs consists in increasing the replication error rate through the use of mutagens. Here, we report about persistent infections of lymphocytic choriomeningitis virus treated with fluorouracil, where a progressive debilitation of infectivity leading to eventual extinction occurs. The transition to extinction is accompanied by the production of large amounts of RNA, indicating that the replicative ability of the quasispecies is not strongly impaired by the mutagen. By means of experimental and theoretical approaches, we propose that a fraction of the RNA molecules synthesized can behave as a defective subpopulation able to drive the viable class extinct. Our results lead to the identification of two extinction pathways, one at high amounts of mutagen, where the quasispecies completely loses its ability to infect and replicate, and a second one, at lower amounts of mutagen, where replication continues while the infective class gets extinct because of the action of defectors. The results bear on a potential application of increased mutagenesis as an antiviral strategy in that low doses of a mutagenic agent may suffice to drive persistent virus to extinction.error catastrophe ͉ mutagen ͉ RNA virus ͉ replicative ability ͉ mathematical model

Exploiting Drug Repositioning for Discovery of a Novel HIV Combination Therapy

“…Since mutagens are not expected to act as chain terminators, no significant decrease in viral DNA would be expected from compounds acting as lethal mutagens. In fact, previous studies have demonstrated that even when mutagens eliminate infectivity, there are still detectable levels of viral RNA (13). This is likely due to the production of defective viruses that are not infectious and can interfere with the infectivity of viruses that were not lethally mutagenized, a process known as lethal defection (13).…”

Pathways to extinction: beyond the error threshold

“…Extinction through lethal defection was first observed in persistent infections of lymphocytic choriomeningitis virus (LCMV) treated with the mutagen 5-fluorouracil (5-FU). About 90 h post-infection, the ability of the virus to produce infective particles disappeared, though its replicative capacity, understood as the capacity of an RNA virus to produce RNA progeny, was not affected (Grande-Pérez et al 2005). The interpretation of the experiment was as follows.…”

“…The production and maintenance of defectors and the selection of different traits in different environments may offer an alternative pathway to extinction, as has been suggested (Grande-Pérez et al 2005) and theoretically demonstrated (Iranzo & Manrubia 2009). The key for a phenotypic trait to become useless requires (i) an environment where that trait is either neutral or not subject to strong selection and (ii) a finite number of individuals in the quasispecies, since extinction through the action of defectors is a purely stochastic phenomenon.…”

“…We believe that the key to use that pathway as an efficient extinction mechanism relies in the identification of environments different from the one where the quasispecies has been optimized and where one basic trait would behave as neutral. In such a situation it could accumulate mutations and create a subpopulation of defectors able to induce the extinction of the whole when confronted again with the first environment (Grande-Pérez et al 2005;Herrera et al 2007).…”

Mixed genotype transmission bodies and virions contribute to the maintenance of diversity in an insect virus

“…Within-host diversity may be achieved when inoculum comprises a diverse pool of virus genomes (Lord et al 1997;Bonneau et al 2001;Cory et al 2005;Herring et al 2005;Jerzak et al 2005), when genotypically distinct viruses cooperate to achieve infection, such as the facilitation observed in homologous or heterologous 'helper viruses' (Eckner 1973;Stenger 1998), or when viruses are capable of generating de novo diversity during the replication process in the newly infected host (Domingo et al 1998;Chang et al 2002;Ló pez-Bueno et al 2003). Genotypic diversity within infected hosts can have dramatic repercussions for both host and virus, including alterations in virulence (harm suffered by the host) (Sedarati et al 1988;Brown et al 2002;Schjørring & Koella 2002;Alizon 2008), within-host population dynamics (Miralles et al 2001;Rauch et al 2008), virus fitness (Hodgson et al 2004;Arends et al 2005;Č ičin-Š ain et al 2005;Simó n et al 2006), and if frequent, may favour the evolution of cheating genotypes (Turner & Chao 1999;Frank 2000;Grande-Pérez et al 2005).…”