Error catastrophe and antiviral strategy

Eigen, Manfred

doi:10.1073/pnas.212514799

Cited by 317 publications

(274 citation statements)

References 16 publications

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“…One such strategy, termed lethal mutagenesis, is based on the theoretical concept of entry into error catastrophe (Eigen, 1971;Eigen et al, 1988;Eigen & Schuster, 1979). According to this concept, for any replicating entity, there is an upper value of the mutation rate, termed the error threshold, which must not be crossed if the wild-type genome distribution is to be kept stable (Biebricher & Eigen, 2005;Eigen, 2002). Applied to viruses, an increase of the mutation rate above some critical value might lead to drift of sequences, disorganization of the quasispecies and, consequently, to loss of infectivity (Eigen, 2002).…”

Section: Introductionmentioning

confidence: 99%

An interfering activity against lymphocytic choriomeningitis virus replication associated with enhanced mutagenesis

Martı́n

Abia

Domingo

et al. 2009

Journal of General Virology

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Previous studies have documented that, in the presence of the mutagenic base analogue 5-fluorouracil (FU), lymphocytic choriomeningitis virus (LCMV) that persisted in BHK-21 cells decreased its infectivity to a larger extent than intracellular viral RNA levels, prior to virus extinction. This observation, together with in silico simulations, led to the proposal of the lethal defection model of virus extinction. This model suggests the participation of defective-interfering genomes in the loss of infectivity by increased mutagenesis. Since LCMV naturally produces defective-interfering particles, it was important to show that a capacity to interfere is produced in association with FU treatment. Here, we document that BHK-21 cells persistently infected with LCMV grown in the presence of FU, but not in its absence, generated an interfering activity that suppressed LCMV infectivity. Interference was specific for LCMV and was sensitive to UV irradiation and its activity was dose-and time-dependent. The interfering preparations produced positive LCMV immunofluorescence and viral particles seen by electron microscopy when used to infect cells, despite some preparations being devoid of detectable infectivity. Interference did not involve significant increases of mutant spectrum complexity, as predicted by the lethal defection model. The results provide support for a specific interference associated with LCMV when the virus replicates in the presence of FU. The excess of interference relative to that observed in the absence of FU is necessary for LCMV extinction.

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Section: Introductionmentioning

confidence: 99%

An interfering activity against lymphocytic choriomeningitis virus replication associated with enhanced mutagenesis

Martı́n

Abia

Domingo

et al. 2009

Journal of General Virology

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“…Hence, this model predicts that above a certain mutation threshold faithful replication of the best adapted genotype is compromised. Moreover, there seems to be general agreement in the biology literature that above this threshold the virus population will go extinct, see Eigen (2002) and Manrubia et al (2010). We propose here a simple stochastic model that shows that this is not necessarily so.…”

Section: Introductionmentioning

confidence: 74%

“…An important current strategy to fight HIV and other viruses is to try to increase the mutation probability of the virus, see Eigen (2002) and Manrubia et al (2010). This assumes that above a certain mutation threshold the virus will die out.…”

Section: Introductionmentioning

confidence: 99%

A Branching Process for Virus Survival

Cox¹,

Schinazi

2012

J. Appl. Probab.

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Abstract. Quasispecies theory predicts that there is a critical mutation probability above which a viral population will go extinct. Above this threshold the virus loses the ability to replicate the best adapted genotype, leading to a population composed of low replicating mutants that is eventually doomed. We propose a new branching model that shows that this is not necessarily so. That is, a population composed of ever changing mutants may survive.

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“…We consider that these interesting results need to be viewed with caution due to the fact that only two MB cell lines were investigated and in some situations the cell response in culture might not always mirror the clinical situation. Nevertheless, further investigation to determinate how CIN could provide no growth advantage and even be deleterious for cancer cell survival through an evolutionary scenario similar to ''mutational meltdown'' in bacteria (Lynch et al 1993) or ''error catastrophe'' in viruses (Eigen 2002), is needed not only in MB cells, but also in many other cancer cell types. Additionally, we believe that understanding the mechanisms underlying CIN could provide insight into the cellular consequences and will reveal the possibility to explore it in MB therapy or other cancers.…”

Section: Discussionmentioning

confidence: 99%

Chromosomal heterogeneity and instability characterize pediatric medulloblastoma cell lines and affect neoplastic phenotype

et al. 2013

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Chromosomal heterogeneity is a hallmark of most tumors and it can drive critical events as growth advantages, survival advantages, progression and karyotypic evolution. Medulloblastoma (MB) is the most common malignant central nervous system tumor in children. This work attempted to investigate chromosomal heterogeneity and instability profiles of two MB pediatric cell lines and their relationship with cell phenotype. We performed GTG-banding and cytokinesis-block micronucleus cytome assays, as well as morphological characterization, cell population doubling time, colony-forming efficiency, and chemo-sensitivity assays in two pediatric MB cell lines (UW402 and UW473). Both MB cells showed a high chromosomal heterogeneity. UW473 cells showed *2 fold higher both clonal-and non-clonal chromosomal alterations than UW402 cells. Besides, UW473 showed two clonal-groups well-differentiated by ploidy level (\2n[and\4n[) and also presented a significantly higher number of chromosomal instability biomarkers. These results were associated with high morphological heterogeneity and survival advantages for UW473 and proliferation advantages for UW402 cells. Moreover, UW473 was significantly more sensitive to methotrexate, temozolomide and cisplatin while UW402 cells were more sensitive to doxorubicin. These data suggest that distinct different degrees of karyotypic heterogeneity and instability may affect neoplasic phenotype of MB cells. These findings bring new insights into cell and tumor biology.

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Error catastrophe and antiviral strategy

Cited by 317 publications

References 16 publications

An interfering activity against lymphocytic choriomeningitis virus replication associated with enhanced mutagenesis

An interfering activity against lymphocytic choriomeningitis virus replication associated with enhanced mutagenesis

A Branching Process for Virus Survival

Chromosomal heterogeneity and instability characterize pediatric medulloblastoma cell lines and affect neoplastic phenotype

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