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Direct-acting antiviral agents (DAAs) are known to interfere with various intracellular stages of the hepatitis C virus (HCV) life cycle and have demonstrated efficacy in treating HCV infection. However, DAA monotherapy can lead to drug resistance due to mutations. This paper explores the impact of DAA therapy on HCV dynamics using a multiscale age-structured partial differential equation (PDE) model that incorporates intracellular viral RNA replication within infected cells and two strains of viruses representing a drug-sensitive strain and a drug-resistant mutant variant, respectively. We derived an equivalent ordinary differential equation (ODE) model from the PDE model to simplify mathematical analysis and numerical simulations. We studied the dynamics of the two virus strains before treatment and investigated the impact of mutations on the evolution kinetics of drug-sensitive and drug-resistant viruses, as well as the competition between the two strains during treatment. We also explored the role of DAAs in blocking HCV RNA replication and releasing new virus particles from cells. During treatment, mutations do not significantly influence the dynamics of various virus strains; however, they can generate low-level HCV that may be completely inhibited due to their poor fitness. The fitness of the mutant strain compared to the drug-sensitive strain determines which strain dominates the virus population. We also investigated the prevalence and drug resistance evolution of HCV variants during DAA treatment.
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Transient, context‐dependent fitness costs accompanying viral resistance in isolates of the marine microalga Micromonas sp. (class Mamiellophyceae)
Abstract Marine microbes are important in biogeochemical cycling, but the nature and magnitude of their contributions are influenced by their associated viruses. In the presence of a lytic virus, cells that have evolved resistance to infection have an obvious fitness advantage over relatives that remain susceptible. However, susceptible cells remain extant in the wild, implying that the evolution of a fitness advantage in one dimension (virus resistance) must be accompanied by a fitness cost in another dimension. Identifying costs of resistance is challenging because fitness is context‐dependent. We examined the context dependence of fitness costs in isolates of the picophytoplankton genusMicromonasand their co‐occurring dsDNA viruses using experimental evolution. After generating 88 resistant lineages from two ancestralMicromonasstrains, each challenged with one of four distinct viral strains, we found resistance led to a 46% decrease in mean growth rate under high irradiance and a 19% decrease under low. After a year in culture, the experimentally selected lines remained resistant, but fitness costs had attenuated. Our results suggest that the cost of resistance inMicromonasis dependent on environmental conditions and the duration of population adaptation, illustrating the dynamic nature of fitness costs of viral resistance among marine protists.
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- PAR ID:
- 10571275
- Publisher / Repository:
- Wiley
- Date Published:
- Journal Name:
- Environmental Microbiology
- Volume:
- 26
- Issue:
- 8
- ISSN:
- 1462-2912
- Format(s):
- Medium: X
- Sponsoring Org:
- National Science Foundation
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- Free Publicly Accessible Full Text
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Accepted Manuscript
- Journal Article:
- https://doi.org/10.1111/1462-2920.16686
