Quasispecies Dynamics in Disease Prevention and Control
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Cited by 3 publications
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Barrier-Independent, Fitness-Associated Differences in Sofosbuvir Efficacy against Hepatitis C Virus
f Sofosbuvir displays a high phenotypic barrier to resistance, and it is a component of several combination therapies for hepatitis C virus (HCV) infections. HCV fitness can be a determinant of decreased sensitivity to direct-acting antiviral agents such as telaprevir or daclatasvir, but fitness-dependent decreased drug sensitivity has not been established for drugs with a high phenotypic barrier to resistance. Low-and high-fitness HCV populations and biological clones derived from them were used to infect Huh-7.5 hepatoma cells. Sofosbuvir efficacy was analyzed by measuring virus progeny production during several passages and by selection of possible sofosbuvir resistance mutations determined by sequencing the NS5B-coding region of the resulting populations. Sofosbuvir exhibited reduced efficacy against high-fitness HCV populations, without the acquisition of sofosbuvirspecific resistance mutations. A reduced sofosbuvir efficacy, similar to that observed with the parental populations, was seen for high-fitness individual biological clones. In independently derived high-fitness HCV populations or clones passaged in the presence of sofosbuvir, M289L was selected as the only substitution in the viral polymerase NS5B. In no case was the sofosbuvir-specific resistance substitution S282T observed. High HCV fitness can lead to decreased sensitivity to sofosbuvir, without the acquisition of specific sofosbuvir resistance mutations. Thus, fitness-dependent drug sensitivity can operate with HCV inhibitors that display a high barrier to resistance. This mechanism may underlie treatment failures not associated with selection of sofosbuvirspecific resistance mutations, linked to in vivo fitness of pretreatment viral populations. Hepatitis C virus (HCV) infection affects about 2.3% of the world population, with treatment and patient management costs being an important burden for health systems (1). Treatment efficacy, quantified as the rate of sustained viral response, has improved markedly with the introduction of direct-acting antiviral agents (DAAs) (2). DAAs include inhibitors of the viral protease NS3-4A (telaprevir [TPV], boceprevir, simeprevir, paritaprevir/ritonavir, asunaprevir, etc.), of nonstructural protein NS5A (daclatasvir [DCV], ledipasvir, ombitasvir, etc.), and the polymerase NS5B (nonnucleoside analogues, such as dasabuvir, and one nucleoside analogue, such as sofosbuvir [SOF]). Many DAAs have been licensed for human use, and others are still in preclinical and clinical assessment.A major issue in antiviral treatments is the selection of inhibitor-resistant mutants leading to treatment failure. Selection is influenced by genetic and phenotypic barriers to resistance. The genetic barrier depends on the number and type of mutations needed for the RNA to encode amino acid substitutions needed to confer resistance. The phenotypic barrier is determined by the fitness cost inflicted upon the virus by the mutations associated with resistance. Barriers vary depending on the nature of the antiviral agent, the viral ...
Barrier-Independent, Fitness-Associated Differences in Sofosbuvir Efficacy against Hepatitis C Virus
f Sofosbuvir displays a high phenotypic barrier to resistance, and it is a component of several combination therapies for hepatitis C virus (HCV) infections. HCV fitness can be a determinant of decreased sensitivity to direct-acting antiviral agents such as telaprevir or daclatasvir, but fitness-dependent decreased drug sensitivity has not been established for drugs with a high phenotypic barrier to resistance. Low-and high-fitness HCV populations and biological clones derived from them were used to infect Huh-7.5 hepatoma cells. Sofosbuvir efficacy was analyzed by measuring virus progeny production during several passages and by selection of possible sofosbuvir resistance mutations determined by sequencing the NS5B-coding region of the resulting populations. Sofosbuvir exhibited reduced efficacy against high-fitness HCV populations, without the acquisition of sofosbuvirspecific resistance mutations. A reduced sofosbuvir efficacy, similar to that observed with the parental populations, was seen for high-fitness individual biological clones. In independently derived high-fitness HCV populations or clones passaged in the presence of sofosbuvir, M289L was selected as the only substitution in the viral polymerase NS5B. In no case was the sofosbuvir-specific resistance substitution S282T observed. High HCV fitness can lead to decreased sensitivity to sofosbuvir, without the acquisition of specific sofosbuvir resistance mutations. Thus, fitness-dependent drug sensitivity can operate with HCV inhibitors that display a high barrier to resistance. This mechanism may underlie treatment failures not associated with selection of sofosbuvirspecific resistance mutations, linked to in vivo fitness of pretreatment viral populations. Hepatitis C virus (HCV) infection affects about 2.3% of the world population, with treatment and patient management costs being an important burden for health systems (1). Treatment efficacy, quantified as the rate of sustained viral response, has improved markedly with the introduction of direct-acting antiviral agents (DAAs) (2). DAAs include inhibitors of the viral protease NS3-4A (telaprevir [TPV], boceprevir, simeprevir, paritaprevir/ritonavir, asunaprevir, etc.), of nonstructural protein NS5A (daclatasvir [DCV], ledipasvir, ombitasvir, etc.), and the polymerase NS5B (nonnucleoside analogues, such as dasabuvir, and one nucleoside analogue, such as sofosbuvir [SOF]). Many DAAs have been licensed for human use, and others are still in preclinical and clinical assessment.A major issue in antiviral treatments is the selection of inhibitor-resistant mutants leading to treatment failure. Selection is influenced by genetic and phenotypic barriers to resistance. The genetic barrier depends on the number and type of mutations needed for the RNA to encode amino acid substitutions needed to confer resistance. The phenotypic barrier is determined by the fitness cost inflicted upon the virus by the mutations associated with resistance. Barriers vary depending on the nature of the antiviral agent, the viral ...
Rift Valley fever virus (RVFV) is an emerging, mosquito-borne, zoonotic pathogen with recurrent outbreaks taking a considerable toll in human deaths in many African countries, for which no effective treatment is available. In cell culture studies and with laboratory animal models, the nucleoside analogue favipiravir (T-705) has demonstrated great potential for the treatment of several seasonal, chronic, and emerging RNA virus infections in humans, suggesting applicability to control some viral outbreaks. Treatment with favipiravir was shown to reduce the infectivity of Rift Valley fever virus both in cell cultures and in experimental animal models, but the mechanism of this protective effect is not understood. In this work, we show that favipiravir at concentrations well below the toxicity threshold estimated for cells is able to extinguish RVFV from infected cell cultures. Nucleotide sequence analysis has documented RVFV mutagenesis associated with virus extinction, with a significant increase in G to A and C to U transition frequencies and a decrease of specific infectivity, hallmarks of lethal mutagenesis.
Viral quasispecies evolution upon long-term virus replication in a noncoevolving cellular environment raises relevant general issues, such as the attainment of population equilibrium, compliance with the molecular-clock hypothesis, or stability of the phenotypic profile. Here, we evaluate the adaptation, mutant spectrum dynamics, and phenotypic diversification of hepatitis C virus (HCV) in the course of 200 passages in human hepatoma cells in an experimental design that precluded coevolution of the cells with the virus. Adaptation to the cells was evidenced by increase in progeny production. The rate of accumulation of mutations in the genomic consensus sequence deviated slightly from linearity, and mutant spectrum analyses revealed a complex dynamic of mutational waves, which was sustained beyond passage 100. The virus underwent several phenotypic changes, some of which impacted the virus-host relationship, such as enhanced cell killing, a shift toward higher virion density, and increased shutoff of host cell protein synthesis. Fluctuations in progeny production and failure to reach population equilibrium at the genomic level suggest internal instabilities that anticipate an unpredictable HCV evolution in the complex liver environment. Long-term virus evolution in an unperturbed cellular environment can reveal features of virus evolution that cannot be explained by comparing natural viral isolates. In the present study, we investigate genetic and phenotypic changes that occur upon prolonged passage of hepatitis C virus (HCV) in human hepatoma cells in an experimental design in which host cell evolutionary change is prevented. Despite replication in a noncoevolving cellular environment, the virus exhibited internal population disequilibria that did not decline with increased adaptation to the host cells. The diversification of phenotypic traits suggests that disequilibria inherent to viral populations may provide a selective advantage to viruses that can be fully exploited in changing environments.
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