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Quasispecies theory and the behavior of RNA viruses.

Lauring AS, Andino R - PLoS Pathog. (2010)

Bottom Line: These viruses replicate with extremely high mutation rates and exhibit significant genetic diversity.For the last 30 years, quasispecies theory has provided a population-based framework for understanding RNA viral evolution.Here, we discuss basic principles of quasispecies theory and describe its relevance for our understanding of viral fitness, virulence, and antiviral therapeutic strategy.

View Article: PubMed Central - PubMed

Affiliation: Department of Medicine, University of California, San Francisco, San Francisco, California, United States of America.

ABSTRACT
A large number of medically important viruses, including HIV, hepatitis C virus, and influenza, have RNA genomes. These viruses replicate with extremely high mutation rates and exhibit significant genetic diversity. This diversity allows a viral population to rapidly adapt to dynamic environments and evolve resistance to vaccines and antiviral drugs. For the last 30 years, quasispecies theory has provided a population-based framework for understanding RNA viral evolution. A quasispecies is a cloud of diverse variants that are genetically linked through mutation, interact cooperatively on a functional level, and collectively contribute to the characteristics of the population. Many predictions of quasispecies theory run counter to traditional views of microbial behavior and evolution and have profound implications for our understanding of viral disease. Here, we discuss basic principles of quasispecies theory and describe its relevance for our understanding of viral fitness, virulence, and antiviral therapeutic strategy.

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Related in: MedlinePlus

Mutant distributions and the error threshold.(A) The majority of viruses in a wild-type population has few mutations and is viable Some viruses, bearing a higher mutational load, are nonviable and considered beyond the threshold of error catastrophe (shown in green). Small increases in mutation frequency, mediated by host APOBEC proteins or exogenous mutagen, push the distribution to the right, past the error threshold. The number of errors per genome is sufficiently high to lethally mutate a majority of the population. (B) A high fidelity polymerase results results in a narrower quasispecies situated farther from the error threshold. This population is more resistant to the effect of mutagen, because it does not accumulate as many mutations, as the wild type does not cross the error threshold. Figure adapted from Crotty et al. [42].
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ppat-1001005-g003: Mutant distributions and the error threshold.(A) The majority of viruses in a wild-type population has few mutations and is viable Some viruses, bearing a higher mutational load, are nonviable and considered beyond the threshold of error catastrophe (shown in green). Small increases in mutation frequency, mediated by host APOBEC proteins or exogenous mutagen, push the distribution to the right, past the error threshold. The number of errors per genome is sufficiently high to lethally mutate a majority of the population. (B) A high fidelity polymerase results results in a narrower quasispecies situated farther from the error threshold. This population is more resistant to the effect of mutagen, because it does not accumulate as many mutations, as the wild type does not cross the error threshold. Figure adapted from Crotty et al. [42].

Mentions: Quasispecies theory accepts this trade-off, and proposes an upper limit to mutation rate, the “error threshold” (Figure 3A). According to Eigen's original formulations, a quasispecies can remain at equilibrium despite a high mutation rate [38], [39]. Small increases in mutation rate will upset this balance as the master sequence itself disappears and meaningful genetic information is lost in an avalanche of errors. Because Eigen compared this process to chemical phase transitions, it has been termed “mutational meltdown.” It is now clear that many RNA viruses replicate near the error threshold. Early studies with VSV showed that chemical mutagens generally reduced viral infectivity, and studies with poliovirus clearly demonstrated that mutagenic nucleoside analogs push viral populations to extinction [40]–[43]. The effect is dramatic—a 4-fold increase in mutation rate resulted in a 95% reduction in viral titer. Others have found similar results with lymphocytic choriomeningitis virus (LCMV) and foot and mouth disease virus (FMDV) [44]–[48]. The lethal mutagenesis of viral populations is perhaps the most important implication of the error threshold.


Quasispecies theory and the behavior of RNA viruses.

Lauring AS, Andino R - PLoS Pathog. (2010)

Mutant distributions and the error threshold.(A) The majority of viruses in a wild-type population has few mutations and is viable Some viruses, bearing a higher mutational load, are nonviable and considered beyond the threshold of error catastrophe (shown in green). Small increases in mutation frequency, mediated by host APOBEC proteins or exogenous mutagen, push the distribution to the right, past the error threshold. The number of errors per genome is sufficiently high to lethally mutate a majority of the population. (B) A high fidelity polymerase results results in a narrower quasispecies situated farther from the error threshold. This population is more resistant to the effect of mutagen, because it does not accumulate as many mutations, as the wild type does not cross the error threshold. Figure adapted from Crotty et al. [42].
© Copyright Policy
Related In: Results  -  Collection

Show All Figures
getmorefigures.php?uid=PMC2908548&req=5

ppat-1001005-g003: Mutant distributions and the error threshold.(A) The majority of viruses in a wild-type population has few mutations and is viable Some viruses, bearing a higher mutational load, are nonviable and considered beyond the threshold of error catastrophe (shown in green). Small increases in mutation frequency, mediated by host APOBEC proteins or exogenous mutagen, push the distribution to the right, past the error threshold. The number of errors per genome is sufficiently high to lethally mutate a majority of the population. (B) A high fidelity polymerase results results in a narrower quasispecies situated farther from the error threshold. This population is more resistant to the effect of mutagen, because it does not accumulate as many mutations, as the wild type does not cross the error threshold. Figure adapted from Crotty et al. [42].
Mentions: Quasispecies theory accepts this trade-off, and proposes an upper limit to mutation rate, the “error threshold” (Figure 3A). According to Eigen's original formulations, a quasispecies can remain at equilibrium despite a high mutation rate [38], [39]. Small increases in mutation rate will upset this balance as the master sequence itself disappears and meaningful genetic information is lost in an avalanche of errors. Because Eigen compared this process to chemical phase transitions, it has been termed “mutational meltdown.” It is now clear that many RNA viruses replicate near the error threshold. Early studies with VSV showed that chemical mutagens generally reduced viral infectivity, and studies with poliovirus clearly demonstrated that mutagenic nucleoside analogs push viral populations to extinction [40]–[43]. The effect is dramatic—a 4-fold increase in mutation rate resulted in a 95% reduction in viral titer. Others have found similar results with lymphocytic choriomeningitis virus (LCMV) and foot and mouth disease virus (FMDV) [44]–[48]. The lethal mutagenesis of viral populations is perhaps the most important implication of the error threshold.

Bottom Line: These viruses replicate with extremely high mutation rates and exhibit significant genetic diversity.For the last 30 years, quasispecies theory has provided a population-based framework for understanding RNA viral evolution.Here, we discuss basic principles of quasispecies theory and describe its relevance for our understanding of viral fitness, virulence, and antiviral therapeutic strategy.

View Article: PubMed Central - PubMed

Affiliation: Department of Medicine, University of California, San Francisco, San Francisco, California, United States of America.

ABSTRACT
A large number of medically important viruses, including HIV, hepatitis C virus, and influenza, have RNA genomes. These viruses replicate with extremely high mutation rates and exhibit significant genetic diversity. This diversity allows a viral population to rapidly adapt to dynamic environments and evolve resistance to vaccines and antiviral drugs. For the last 30 years, quasispecies theory has provided a population-based framework for understanding RNA viral evolution. A quasispecies is a cloud of diverse variants that are genetically linked through mutation, interact cooperatively on a functional level, and collectively contribute to the characteristics of the population. Many predictions of quasispecies theory run counter to traditional views of microbial behavior and evolution and have profound implications for our understanding of viral disease. Here, we discuss basic principles of quasispecies theory and describe its relevance for our understanding of viral fitness, virulence, and antiviral therapeutic strategy.

Show MeSH
Related in: MedlinePlus