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

Iranzo, Jaime; Perales, Celia; Domingo, Esteban; Manrubia, Susanna C.

doi:10.1073/pnas.1110489108

Cited by 35 publications

(44 citation statements)

References 38 publications

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“…Thus, IFN-␣-resistant HCV populations may provide a useful tool to penetrate some aspects of HCV biology that were previously beyond the reach of replicon-based systems. The use of IFN-␣-resistant HCV populations and large HCV populations that may mimic a persistent chronic infection would also be a valuable tool in the design of new antivirals or the testing of new antiviral regimens based on lethal mutagenesis (127,128).…”

Section: Discussionmentioning

confidence: 99%

Response of Hepatitis C Virus to Long-Term Passage in the Presence of Alpha Interferon: Multiple Mutations and a Common Phenotype

Perales

Beach

Gallego

et al. 2013

J Virol

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172

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H epatitis C virus (HCV) infects an estimated 180 million people worldwide, and about 75% of newly infected patients progress toward a chronic infection, which constitutes a risk for severe liver diseases such as cirrhosis and hepatocarcinoma (1-4). HCV is a hepacivirus in the Flaviviridae family characterized by the error-prone replication and quasispecies dynamics typical of RNA viruses (2,(5)(6)(7). No vaccine is available to prevent HCV infections or disease, and the current standard of care treatment consists of the combination of pegylated alpha interferon (IFN-␣) and the purine nucleoside analogue ribavirin (1-␤-D-ribofuranosyl-1-H-1,2,4-triazole-3-carboxamide) (8-10). Type I interferons (IFNs) such as IFN-␣ are members of a family of cytokines that constitute key components of the innate immune response to viruses, and their induction results in an antiviral state of the cell and suppression of viral replication (11)(12)(13)(14). Ribavirin is currently used to treat a number of human viral infections, and it can display multiple mechanisms of action, including enhancement of Th1 antiviral immune responses, upregulation of IFN-stimulated genes (ISGs), depletion of GTP pools, or viral RNA mutagenesis (see reviews in references 15, 16 and 17). However, on average only about 60% of the chronically infected patients show a sustained virological response to treatment with IFN-␣ plus ribavirin that results in virus clearance (18-21). The molecular and physiological bases of the therapeutic activity of the current combination treatment with IFN-␣ plus ribavirin are poorly understood. It might be possible to establish new treatment protocols based on recently developed directly acting antiviral agents (DAAs), with or without .Highly variable viruses exploit a number of strategies to counteract selective constraints intended to prevent their replication (reviewed in reference 7). Mutations that confer resistance to DAAs generally map in the target protein or in a protein that interacts with the target (28-30). However, the complexity of the cellular IFN response pathway is expected to require greater diversity of viral resistance mutations. Current evidence suggests that the response of HCV to IFN-␣-based therapy is influenced by several host (i.e., interleukin-28B [IL-28B] gene polymorphisms) and viral genetic (i.e., viral genotype and population complexity) factors (31-37).The advent of cell culture systems for sustained replication of HCV offers new prospects to approach the evolutionary dynamics of HCV and the host cell-virus relationship, including the anti-HCV activity of IFN-␣. Using these systems, Garaigorta and Chisari documented that HCV-induced protein kinase R (PKR) phosphorylation inhibited translation of IFN-stimulated genes (ISGs) in infected hepatocytes (38). Here we describe the adaptation of the HCV replication system of genotype 2a (39-41) to perform serial passages of HCV in the Huh-7.5 hepatocyte cell line with sustained, efficient viral replication for at least 100 serial passages. This cell ...

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Section: Discussionmentioning

confidence: 99%

Response of Hepatitis C Virus to Long-Term Passage in the Presence of Alpha Interferon: Multiple Mutations and a Common Phenotype

Perales

Beach

Gallego

et al. 2013

J Virol

Self Cite

172

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“…Thus, while it is possible to obtain a ribavirin-resistant mutant when it is subjected to serial passages in the presence of increasing concentrations of ribavirin (Sierra et al 2007), when faced with high concentrations of ribavirin from the start, the virus does not dominate and the population becomes extinct (Perales et al 2009). Another example of this effect is the change in the result with respect to interactions with other drugs, such as replication inhibitors (Iranzo et al 2011). In this case, it can be seen that the combined action of certain dosages of mutagens and inhibitors is antagonistic-the mutagen diminishes the effect of the inhibitor-instead of synergistic due, mainly, to the increased probability that mutants resistant to the inhibitor will appear.…”

Section: Sublethal Mutagenesismentioning

confidence: 97%

Theories of Lethal Mutagenesis: From Error Catastrophe to Lethal Defection

Tejero

Montero

Nuño

2015

Current Topics in Microbiology and Immunology

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RNA viruses get extinct in a process called lethal mutagenesis when subjected to an increase in their mutation rate, for instance, by the action of mutagenic drugs. Several approaches have been proposed to understand this phenomenon. The extinction of RNA viruses by increased mutational pressure was inspired by the concept of the error threshold. The now classic quasispecies model predicts the existence of a limit to the mutation rate beyond which the genetic information of the wild type could not be efficiently transmitted to the next generation. This limit was called the error threshold, and for mutation rates larger than this threshold, the quasispecies was said to enter into error catastrophe. This transition has been assumed to foster the extinction of the whole population. Alternative explanations of lethal mutagenesis have been proposed recently. In the first place, a distinction is made between the error threshold and the extinction threshold, the mutation rate beyond which a population gets extinct. Extinction is explained from the effect the mutation rate has, throughout the mutational load, on the reproductive ability of the whole population. Secondly, lethal defection takes also into account the effect of interactions within mutant spectra, which have been shown to be determinant for the understanding the extinction of RNA virus due to an augmented mutational pressure. Nonetheless, some relevant issues concerning lethal mutagenesis are not completely understood yet, as so survival of the flattest, i.e. the development of resistance to lethal mutagenesis by evolving towards mutationally more robust regions of sequence space, or sublethal mutagenesis, i.e., the increase of the mutation rate below the extinction threshold which may boost the adaptability of RNA virus, increasing their ability to develop resistance to drugs (including mutagens). A better design of antiviral therapies will still require an improvement of our knowledge about lethal mutagenesis.

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“…The existence of such a threshold is a central prediction of the quasispecies theory pioneered by Eigen (1) and Swetina and Schuster (2). The recent experimental demonstration of lethal mutagenesis (3)(4)(5), in which an error catastrophe transition is caused by mutagens, demonstrates that key features of the balance of mutation and selection in viruses are elegantly captured by the quasispecies theory.…”

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confidence: 99%

A quantitative quasispecies theory-based model of virus escape mutation under immune selection

Woo

Reifman

2012

Proc. Natl. Acad. Sci. U.S.A.

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Viral infections involve a complex interplay of the immune response and escape mutation of the virus quasispecies inside a single host. Although fundamental aspects of such a balance of mutation and selection pressure have been established by the quasispecies theory decades ago, its implications have largely remained qualitative. Here, we present a quantitative approach to model the virus evolution under cytotoxic T-lymphocyte immune response. The virus quasispecies dynamics are explicitly represented by mutations in the combined sequence space of a set of epitopes within the viral genome. We stochastically simulated the growth of a viral population originating from a single wild-type founder virus and its recognition and clearance by the immune response, as well as the expansion of its genetic diversity. Applied to the immune escape of a simian immunodeficiency virus epitope, model predictions were quantitatively comparable to the experimental data. Within the model parameter space, we found two qualitatively different regimes of infectious disease pathogenesis, each representing alternative fates of the immune response: It can clear the infection in finite time or eventually be overwhelmed by viral growth and escape mutation. The latter regime exhibits the characteristic disease progression pattern of human immunodeficiency virus, while the former is bounded by maximum mutation rates that can be suppressed by the immune response. Our results demonstrate that, by explicitly representing epitope mutations and thus providing a genotype–phenotype map, the quasispecies theory can form the basis of a detailed sequence-specific model of real-world viral pathogens evolving under immune selection.

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

Cited by 35 publications

References 38 publications

Response of Hepatitis C Virus to Long-Term Passage in the Presence of Alpha Interferon: Multiple Mutations and a Common Phenotype

Response of Hepatitis C Virus to Long-Term Passage in the Presence of Alpha Interferon: Multiple Mutations and a Common Phenotype

Theories of Lethal Mutagenesis: From Error Catastrophe to Lethal Defection

A quantitative quasispecies theory-based model of virus escape mutation under immune selection

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