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    In Vivo Emergence of a Novel Protease Inhibitor Resistance Signature in HIV-1 Matrix

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    Author
    Datir, Rawlings
    Kemp, Steven
    El Bouzidi, Kate
    Mlchocova, Petra
    Goldstein, Richard
    Breuer, Judy
    Towers, Greg J
    Jolly, Clare
    Quiñones-Mateu, Miguel E
    Dakum, Patrick S
    Ndembi, Nicaise
    Gupta, Ravindra K
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    Date
    2020-11-03
    Journal
    mBio
    Publisher
    American Society for Microbiology
    Type
    Article
    
    Metadata
    Show full item record
    See at
    https://doi.org/10.1128/mBio.02036-20
    Abstract
    Protease inhibitors (PIs) are the second- and last-line therapy for the majority of HIV-infected patients worldwide. Only around 20% of individuals who fail PI regimens develop major resistance mutations in protease. We sought to explore the role of mutations in gag-pro genotypic and phenotypic changes in viruses from six Nigerian patients who failed PI-based regimens without known drug resistance-associated protease mutations in order to identify novel determinants of PI resistance. Target enrichment and next-generation sequencing (NGS) with the Illumina MiSeq system were followed by haplotype reconstruction. Full-length Gag-protease gene regions were amplified from baseline (pre-PI) and virologic failure (VF) samples, sequenced, and used to construct gag-pro-pseudotyped viruses. Phylogenetic analysis was performed using maximum-likelihood methods. Susceptibility to lopinavir (LPV) and darunavir (DRV) was measured using a single-cycle replication assay. Western blotting was used to analyze Gag cleavage. In one of six participants (subtype CRF02_AG), we found 4-fold-lower LPV susceptibility in viral clones during failure of second-line treatment. A combination of four mutations (S126del, H127del, T122A, and G123E) in the p17 matrix of baseline virus generated a similar 4-fold decrease in susceptibility to LPV but not darunavir. These four amino acid changes were also able to confer LPV resistance to a subtype B Gag-protease backbone. Western blotting demonstrated significant Gag cleavage differences between sensitive and resistant isolates in the presence of drug. Resistant viruses had around 2-fold-lower infectivity than sensitive clones in the absence of drug. NGS combined with haplotype reconstruction revealed that resistant, less fit clones emerged from a minority population at baseline and thereafter persisted alongside sensitive fitter viruses. We used a multipronged genotypic and phenotypic approach to document emergence and temporal dynamics of a novel protease inhibitor resistance signature in HIV-1 matrix, revealing the interplay between Gag-associated resistance and fitness.
    Rights/Terms
    Copyright © 2020 Datir et al.
    Keyword
    Africa
    Gag
    HIV
    antiretroviral
    antiretroviral resistance
    drug
    human immunodeficiency virus
    protease
    protease inhibitors
    proteases
    resistance
    Show allShow less
    Identifier to cite or link to this item
    http://hdl.handle.net/10713/14110
    ae974a485f413a2113503eed53cd6c53
    10.1128/mBio.02036-20
    Scopus Count
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