ArticlePLoS genetics2020
Predominance of positive epistasis among drug resistance-associated mutations in HIV-1 protease.
Article in PLoS genetics, 2020. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 26 papers.
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Who cites it
26 citing papers in PubMed, 36 citations in OpenAlex.
- Scanning the horizon: deep mutational scanning approaches in virology.Journal of virology · 2026Review
- Different mechanisms for human rhinovirus survival in the presence of deleterious amino acid substitutions at virion protein-protein or RNA-protein interfaces.Journal of virology · 2026Article
- Narrowed host ranges do not constrain future host range expansion in RNA phage Φ6.Journal of virology · 2026Article
- Article
- Coevolutionary history of predation constrains the evolvability of antibiotic resistance in prey bacteria.npj antimicrobials and resistance · 2025Article
- Review
- Machine learning-based prediction of bioactivity in HIV-1 protease: insights from electron density analysis.Future medicinal chemistry · 2024Article
- Efficient epistasis inference via higher-order covariance matrix factorization.bioRxiv : the preprint server for biology · 2024Article
- Deep mutational scanning quantifies DNA binding and predicts clinical outcomes of PAX6 variants.Molecular systems biology · 2024Article
- In vivo functional phenotypes from a computational epistatic model of evolution.Proceedings of the National Academy of Sciences of the United States of America · 2024Article
- Changing selection on amino acid substitutions in Gag protein between major HIV-1 subtypes.Virus evolution · 2024Article
- Direct-acting antiviral resistance of Hepatitis C virus is promoted by epistasis.Nature communications · 2023Article
- Mechanisms of HIV-1 integrase resistance to dolutegravir and potent inhibition of drug-resistant variants.Science advances · 2023Article
- HCV E1 influences the fitness landscape of E2 and may enhance escape from E2-specific antibodies.Virus evolution · 2023Article
- Development and validation of a scoring system for the prediction of HIV drug resistance in Hubei province, China.Frontiers in cellular and infection microbiology · 2023Article
- Contingency and Entrenchment of Drug-Resistance Mutations in HIV Viral Proteins.The journal of physical chemistry. B · 2022Article
- Viral proteases as therapeutic targets.Molecular aspects of medicine · 2022Review
- Inferring Epistasis from Genetic Time-series Data.Molecular biology and evolution · 2022Article
- Intragenic compensation through the lens of deep mutational scanning.Biophysical reviews · 2022Review
- Design of an optimal combination therapy with broadly neutralizing antibodies to suppress HIV-1.eLife · 2022Article
Corrections and comments
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Authors and funding
9 authors at 5 institutions in 2 countries.
Funding
Abstract
Drug-resistant mutations often have deleterious impacts on replication fitness, posing a fitness cost that can only be overcome by compensatory mutations. However, the role of fitness cost in the evolution of drug resistance has often been overlooked in clinical studies or in vitro selection experiments, as these observations only capture the outcome of drug selection. In this study, we systematically profile the fitness landscape of resistance-associated sites in HIV-1 protease using deep mutational scanning. We construct a mutant library covering combinations of mutations at 11 sites in HIV-1 protease, all of which are associated with resistance to protease inhibitors in clinic. Using deep sequencing, we quantify the fitness of thousands of HIV-1 protease mutants after multiple cycles of replication in human T cells. Although the majority of resistance-associated mutations have deleterious effects on viral replication, we find that epistasis among resistance-associated mutations is predominantly positive. Furthermore, our fitness data are consistent with genetic interactions inferred directly from HIV sequence data of patients. Fitness valleys formed by strong positive epistasis reduce the likelihood of reversal of drug resistance mutations. Overall, our results support the view that strong compensatory effects are involved in the emergence of clinically observed resistance mutations and provide insights to understanding fitness barriers in the evolution and reversion of drug resistance.
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