Quantifying the Evolutionary Constraints and Potential of Hepatitis C Virus NS5A Protein

ABSTRACT RNA viruses, such as hepatitis C virus (HCV), influenza virus, and SARS-CoV-2, are notorious for their ability to evolve rapidly under selection in novel environments. It is known that the high mutation rate of RNA viruses can generate huge genetic diversity to facilitate viral adaptation....

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Autores principales:	Lei Dai, Yushen Du, Hangfei Qi, Christian D. Huber, Dongdong Chen, Tian-Hao Zhang, Nicholas C. Wu, Ergang Wang, James O. Lloyd-Smith, Ren Sun
Formato:	article
Lenguaje:	EN
Publicado:	American Society for Microbiology 2021
Materias:	DFE deep mutational scanning drug resistance fitness landscape HCV viral evolution Microbiology QR1-502
Acceso en línea:	https://doaj.org/article/a2ace3edb4d846629c7852193d0d3111
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spelling	oai:doaj.org-article:a2ace3edb4d846629c7852193d0d31112021-12-02T17:07:47ZQuantifying the Evolutionary Constraints and Potential of Hepatitis C Virus NS5A Protein10.1128/mSystems.01111-202379-5077https://doaj.org/article/a2ace3edb4d846629c7852193d0d31112021-04-01T00:00:00Zhttps://journals.asm.org/doi/10.1128/mSystems.01111-20https://doaj.org/toc/2379-5077ABSTRACT RNA viruses, such as hepatitis C virus (HCV), influenza virus, and SARS-CoV-2, are notorious for their ability to evolve rapidly under selection in novel environments. It is known that the high mutation rate of RNA viruses can generate huge genetic diversity to facilitate viral adaptation. However, less attention has been paid to the underlying fitness landscape that represents the selection forces on viral genomes, especially under different selection conditions. Here, we systematically quantified the distribution of fitness effects of about 1,600 single amino acid substitutions in the drug-targeted region of NS5A protein of HCV. We found that the majority of nonsynonymous substitutions incur large fitness costs, suggesting that NS5A protein is highly optimized. The replication fitness of viruses is correlated with the pattern of sequence conservation in nature, and viral evolution is constrained by the need to maintain protein stability. We characterized the adaptive potential of HCV by subjecting the mutant viruses to selection by the antiviral drug daclatasvir at multiple concentrations. Both the relative fitness values and the number of beneficial mutations were found to increase with the increasing concentrations of daclatasvir. The changes in the spectrum of beneficial mutations in NS5A protein can be explained by a pharmacodynamics model describing viral fitness as a function of drug concentration. Overall, our results show that the distribution of fitness effects of mutations is modulated by both the constraints on the biophysical properties of proteins (i.e., selection pressure for protein stability) and the level of environmental stress (i.e., selection pressure for drug resistance). IMPORTANCE Many viruses adapt rapidly to novel selection pressures, such as antiviral drugs. Understanding how pathogens evolve under drug selection is critical for the success of antiviral therapy against human pathogens. By combining deep sequencing with selection experiments in cell culture, we have quantified the distribution of fitness effects of mutations in hepatitis C virus (HCV) NS5A protein. Our results indicate that the majority of single amino acid substitutions in NS5A protein incur large fitness costs. Simulation of protein stability suggests viral evolution is constrained by the need to maintain protein stability. By subjecting the mutant viruses to selection under an antiviral drug, we find that the adaptive potential of viral proteins in a novel environment is modulated by the level of environmental stress, which can be explained by a pharmacodynamics model. Our comprehensive characterization of the fitness landscapes of NS5A can potentially guide the design of effective strategies to limit viral evolution.Lei DaiYushen DuHangfei QiChristian D. HuberDongdong ChenTian-Hao ZhangNicholas C. WuErgang WangJames O. Lloyd-SmithRen SunAmerican Society for MicrobiologyarticleDFEdeep mutational scanningdrug resistancefitness landscapeHCVviral evolutionMicrobiologyQR1-502ENmSystems, Vol 6, Iss 2 (2021)
institution	DOAJ
collection	DOAJ
language	EN
topic	DFE deep mutational scanning drug resistance fitness landscape HCV viral evolution Microbiology QR1-502
spellingShingle	DFE deep mutational scanning drug resistance fitness landscape HCV viral evolution Microbiology QR1-502 Lei Dai Yushen Du Hangfei Qi Christian D. Huber Dongdong Chen Tian-Hao Zhang Nicholas C. Wu Ergang Wang James O. Lloyd-Smith Ren Sun Quantifying the Evolutionary Constraints and Potential of Hepatitis C Virus NS5A Protein
description	ABSTRACT RNA viruses, such as hepatitis C virus (HCV), influenza virus, and SARS-CoV-2, are notorious for their ability to evolve rapidly under selection in novel environments. It is known that the high mutation rate of RNA viruses can generate huge genetic diversity to facilitate viral adaptation. However, less attention has been paid to the underlying fitness landscape that represents the selection forces on viral genomes, especially under different selection conditions. Here, we systematically quantified the distribution of fitness effects of about 1,600 single amino acid substitutions in the drug-targeted region of NS5A protein of HCV. We found that the majority of nonsynonymous substitutions incur large fitness costs, suggesting that NS5A protein is highly optimized. The replication fitness of viruses is correlated with the pattern of sequence conservation in nature, and viral evolution is constrained by the need to maintain protein stability. We characterized the adaptive potential of HCV by subjecting the mutant viruses to selection by the antiviral drug daclatasvir at multiple concentrations. Both the relative fitness values and the number of beneficial mutations were found to increase with the increasing concentrations of daclatasvir. The changes in the spectrum of beneficial mutations in NS5A protein can be explained by a pharmacodynamics model describing viral fitness as a function of drug concentration. Overall, our results show that the distribution of fitness effects of mutations is modulated by both the constraints on the biophysical properties of proteins (i.e., selection pressure for protein stability) and the level of environmental stress (i.e., selection pressure for drug resistance). IMPORTANCE Many viruses adapt rapidly to novel selection pressures, such as antiviral drugs. Understanding how pathogens evolve under drug selection is critical for the success of antiviral therapy against human pathogens. By combining deep sequencing with selection experiments in cell culture, we have quantified the distribution of fitness effects of mutations in hepatitis C virus (HCV) NS5A protein. Our results indicate that the majority of single amino acid substitutions in NS5A protein incur large fitness costs. Simulation of protein stability suggests viral evolution is constrained by the need to maintain protein stability. By subjecting the mutant viruses to selection under an antiviral drug, we find that the adaptive potential of viral proteins in a novel environment is modulated by the level of environmental stress, which can be explained by a pharmacodynamics model. Our comprehensive characterization of the fitness landscapes of NS5A can potentially guide the design of effective strategies to limit viral evolution.
format	article
author	Lei Dai Yushen Du Hangfei Qi Christian D. Huber Dongdong Chen Tian-Hao Zhang Nicholas C. Wu Ergang Wang James O. Lloyd-Smith Ren Sun
author_facet	Lei Dai Yushen Du Hangfei Qi Christian D. Huber Dongdong Chen Tian-Hao Zhang Nicholas C. Wu Ergang Wang James O. Lloyd-Smith Ren Sun
author_sort	Lei Dai
title	Quantifying the Evolutionary Constraints and Potential of Hepatitis C Virus NS5A Protein
title_short	Quantifying the Evolutionary Constraints and Potential of Hepatitis C Virus NS5A Protein
title_full	Quantifying the Evolutionary Constraints and Potential of Hepatitis C Virus NS5A Protein
title_fullStr	Quantifying the Evolutionary Constraints and Potential of Hepatitis C Virus NS5A Protein
title_full_unstemmed	Quantifying the Evolutionary Constraints and Potential of Hepatitis C Virus NS5A Protein
title_sort	quantifying the evolutionary constraints and potential of hepatitis c virus ns5a protein
publisher	American Society for Microbiology
publishDate	2021
url	https://doaj.org/article/a2ace3edb4d846629c7852193d0d3111
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Quantifying the Evolutionary Constraints and Potential of Hepatitis C Virus NS5A Protein

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