In Vivo Emergence of a Novel Protease Inhibitor Resistance Signature in HIV-1 Matrix
dc.contributor.author | Datir, Rawlings | |
dc.contributor.author | Kemp, Steven | |
dc.contributor.author | El Bouzidi, Kate | |
dc.contributor.author | Mlchocova, Petra | |
dc.contributor.author | Goldstein, Richard | |
dc.contributor.author | Breuer, Judy | |
dc.contributor.author | Towers, Greg J | |
dc.contributor.author | Jolly, Clare | |
dc.contributor.author | Quiñones-Mateu, Miguel E | |
dc.contributor.author | Dakum, Patrick S | |
dc.contributor.author | Ndembi, Nicaise | |
dc.contributor.author | Gupta, Ravindra K | |
dc.date.accessioned | 2020-11-18T17:50:23Z | |
dc.date.available | 2020-11-18T17:50:23Z | |
dc.date.issued | 2020-11-03 | |
dc.identifier.uri | http://hdl.handle.net/10713/14110 | |
dc.description.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. | en_US |
dc.description.uri | https://doi.org/10.1128/mBio.02036-20 | en_US |
dc.language.iso | en | en_US |
dc.publisher | American Society for Microbiology | en_US |
dc.relation.ispartof | mBio | en_US |
dc.rights | Copyright © 2020 Datir et al. | en_US |
dc.subject | Africa | en_US |
dc.subject | Gag | en_US |
dc.subject | HIV | en_US |
dc.subject | antiretroviral | en_US |
dc.subject | antiretroviral resistance | en_US |
dc.subject | drug | en_US |
dc.subject | human immunodeficiency virus | en_US |
dc.subject | protease | en_US |
dc.subject | protease inhibitors | en_US |
dc.subject | proteases | en_US |
dc.subject | resistance | en_US |
dc.title | In Vivo Emergence of a Novel Protease Inhibitor Resistance Signature in HIV-1 Matrix | en_US |
dc.type | Article | en_US |
dc.identifier.doi | 10.1128/mBio.02036-20 | |
dc.identifier.pmid | 33144375 | |
dc.source.volume | 11 | |
dc.source.issue | 6 | |
dc.source.country | United States |