ArticleComputational and structural biotechnology journal2021
The impact of Gag non-cleavage site mutations on HIV-1 viral fitness from integrative modelling and simulations.
Article in Computational and structural biotechnology journal, 2021. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 8 papers.
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Who cites it
8 citing papers in PubMed, 11 citations in OpenAlex.
- A detailed characterization of drug resistance during darunavir/ritonavir monotherapy highlights a high barrier to the emergence of resistance mutations in protease but identifies alternative pathways of resistance.The Journal of antimicrobial chemotherapy · 2024Trial
- Research progress on HIV-1 structural proteins and antiviral therapies.Frontiers in immunology · 2026Review
- Noncanonical HIV drug resistance mutations: need to close existing gaps.AIDS (London, England) · 2025Review
- The HIV-1 Gag Protein Displays Extensive Functional and Structural Roles in Virus Replication and Infectivity.International journal of molecular sciences · 2022Review
- Sagacious epitope selection for vaccines, and both antibody-based therapeutics and diagnostics: tips from virology and oncology.Antibody therapeutics · 2022Review
- Integrative structural biology of HIV-1 capsid protein assemblies: combining experiment and computation.Current opinion in virology · 2021Review
- Spontaneous Mutations in HIV-1 Gag, Protease, RT p66 in the First Replication Cycle and How They Appear: Insights from an In Vitro Assay on Mutation Rates and Types.International journal of molecular sciences · 2020Article
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Authors and funding
3 authors at 1 institution in 2 countries.
Funding
No grant is acknowledged in the PubMed record.
Abstract
The high mutation rate in retroviruses is one of the leading causes of drug resistance. In human immunodeficiency virus type-1 (HIV-1), synergistic mutations in its protease and the protease substrate - the Group-specific antigen (Gag) polyprotein - work together to confer drug resistance against protease inhibitors and compensate the mutations affecting viral fitness. Some Gag mutations can restore Gag-protease binding, yet most Gag-protease correlated mutations occur outside of the Gag cleavage site. To investigate the molecular basis for this, we now report multiscale modelling approaches to investigate various sequentially cleaved Gag products in the context of clinically relevant mutations that occur outside of the cleavage sites, including simulations of the largest Gag proteolytic product in its viral membrane-bound state. We found that some mutations, such as G123E and H219Q, involve direct interaction with cleavage site residues to influence their local environment, while certain mutations in the matrix domain lead to the enrichment of lipids important for Gag targeting and assembly. Collectively, our results reveal why non-cleavage site mutations have far-reaching implications outside of Gag proteolysis, with important consequences for drugging Gag maturation intermediates and tackling protease inhibitor resistance.
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Registered trials
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