{"doi":"10.1128/msystems.01111-20","title":"Quantifying the Evolutionary Constraints and Potential of Hepatitis C Virus NS5A Protein","abstract":"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.","journal":"mSystems","year":2021,"id":202312,"datarank":0.0,"base_score":0.0,"endowment":0.0,"self_citation_contribution":0.0,"citation_network_contribution":0.0,"self_endowment_contribution":0.0,"citer_contribution":0.0,"corpus_percentile":null,"corpus_rank":null,"citation_count":6,"citer_count":0,"citers_with_citation_signal":0,"citers_with_endowment":0,"datacite_reuse_total":0,"is_dataset":false,"is_dataset_confidence":0.9435,"is_data_producer":false,"deposit_databanks":null,"is_oa":true,"file_count":0,"downloads":0,"has_version_chain":false,"published_date":"2021-01-01","fair_score":null,"fair_percentile":null,"algorithm_id":"datarank_citation_only_1hop_v6","ranking_scope":"data_only","authors":[{"id":369358,"name":"Yushen Du","orcid":"0000-0002-8015-4207","position":1,"is_corresponding":false},{"id":781910,"name":"Hangfei Qi","orcid":"0000-0001-7822-781X","position":2,"is_corresponding":false},{"id":51378,"name":"Christian D. Huber","orcid":"0000-0002-2267-2604","position":3,"is_corresponding":false},{"id":781911,"name":"Dongdong Chen","orcid":"0000-0003-4747-8880","position":4,"is_corresponding":false},{"id":487179,"name":"Tianhao Zhang","orcid":"0000-0003-3456-8262","position":5,"is_corresponding":false},{"id":105424,"name":"Nicholas C. Wu","orcid":"0000-0002-9078-6697","position":6,"is_corresponding":false},{"id":781912,"name":"Ergang Wang","orcid":"0000-0002-4942-3771","position":7,"is_corresponding":false},{"id":237185,"name":"James O. Lloyd‐Smith","orcid":"0000-0001-7941-502X","position":8,"is_corresponding":false},{"id":107930,"name":"Ren Sun","orcid":"0000-0002-8628-7019","position":9,"is_corresponding":false},{"id":34347,"name":"Lei Dai","orcid":"0000-0002-5598-5308","position":0,"is_corresponding":true}],"reference_count":92,"raw_metadata":null,"created_at":"2026-07-18T23:51:05.955461Z","pmid":"33850042","pmcid":null,"fwci":null,"citation_percentile":null,"influential_citations":0,"oa_status":null,"license":null,"views":0,"total_file_size_bytes":0,"version_count":0,"fair_f":null,"fair_a":null,"fair_i":null,"fair_r":null,"fair_zscore":null,"fair_rationale":null,"fair_model":null,"fair_agent_version":null,"fair_fulltext_source":null,"fair_has_llm":null,"fair_computed_at":null,"clinical_trials":[],"software_tools":[],"db_accessions":[],"linked_datasets":[],"topics":[]}