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- W3110859215 abstract "Summary 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." @default.
- W3110859215 created "2020-12-21" @default.
- W3110859215 creator A5001674990 @default.
- W3110859215 creator A5038527769 @default.
- W3110859215 creator A5041438560 @default.
- W3110859215 date "2020-07-05" @default.
- W3110859215 modified "2023-10-17" @default.
- W3110859215 title "The Impact of Gag Non-Cleavage Site Mutations on HIV-1 Viral Fitness from Integrative Modelling and Simulations" @default.
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- W3110859215 doi "https://doi.org/10.1101/2020.07.05.188326" @default.
- W3110859215 hasPublicationYear "2020" @default.
- W3110859215 type Work @default.