2019
DOI: 10.1101/837120
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Selection of HIV-1 for Resistance to Fifth Generation Protease Inhibitors Reveals Two Independent Pathways to High-Level Resistance

Abstract: 23Well-designed viral protease inhibitors (PIs) potently inhibit replication as well as create 24 a high genetic barrier for resistance. Through in vivo selective pressure, we have generated 25 high-level resistance against ten HIV-1 PIs and their precursor, the FDA-approved drug 26 darunavir (DRV), achieving 1,000-fold resistance over the starting EC50. The accumulation of 27 mutations revealed two pathways to high-level resistance, resulting in protease variants with up 28 to 14 mutations in and outside of t… Show more

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Cited by 3 publications
(14 citation statements)
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“…26,27 Most substitutions in these resistant variants are distal from the inhibitor binding site. S1) Cluster 3 included all variants obtained from viral passaging experiments with DRV and DRV analogs 14 . Cluster 2 included variants with less than 5 amino acid substitutions.…”
Section: Resultsmentioning
confidence: 99%
See 3 more Smart Citations
“…26,27 Most substitutions in these resistant variants are distal from the inhibitor binding site. S1) Cluster 3 included all variants obtained from viral passaging experiments with DRV and DRV analogs 14 . Cluster 2 included variants with less than 5 amino acid substitutions.…”
Section: Resultsmentioning
confidence: 99%
“…HIV-1 protease variants and experimental inhibitor potency Drug resistant variants of HIV-1 protease were obtained from viral passaging experiments with DRV and closely related analogs. 50 These variants were supplemented with variants bearing known primary active site mutations. The crystal structures of wild type protease, variants with primary resistance mutations, and highly drug resistant variants bound to DRV had been determined previously.…”
Section: Data Curationmentioning
confidence: 99%
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“…The protease variants clustered into 3 major subgroups based on amino acid sequence. (Fig 1C, Table S1) Cluster 3 included all variants obtained from viral passaging experiments with DRV and DRV analogs 14 . Cluster 2 included variants with less than 5 amino acid substitutions.…”
Section: Figurementioning
confidence: 99%