Unravelling the dynamics of selection of multiresistant variants to integrase inhibitors in an HIV-1-infected child using ultra-deep sequencing
| Autor: | Louis Bernard, Maud Salmona, Francis Barin, Zoha Maakaroun-Vermesse, Marion Splittgerber, Marie-Laure Chaix, Karl Stefic, Marisa Capitao, Marie-Laure Néré, Constance Delaugerre |
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| Rok vydání: | 2016 |
| Předmět: |
0301 basic medicine
Microbiology (medical) Pyridones Integrase inhibitor HIV Infections HIV Integrase Quinolones Piperazines 03 medical and health sciences chemistry.chemical_compound symbols.namesake Raltegravir Potassium Drug Resistance Viral Oxazines medicine Humans Pharmacology (medical) HIV Integrase Inhibitors Selection Genetic Child Gene Pharmacology Sanger sequencing Genetics biology Elvitegravir High-Throughput Nucleotide Sequencing Raltegravir Resistance mutation Virology Pyrrolidinones Integrase 030104 developmental biology Infectious Diseases chemistry Mutation Dolutegravir HIV-1 biology.protein symbols RNA Viral Heterocyclic Compounds 3-Ring medicine.drug |
| Zdroj: | Journal of Antimicrobial Chemotherapy. :dkw507 |
| ISSN: | 1460-2091 0305-7453 |
| Popis: | Background Ultra-deep sequencing (UDS) allows detection of minority resistant variants (MRVs) with a threshold of 1% and could be useful to identify variants harbouring single or multiple drug-resistance mutations (DRMs). Objectives We analysed the integrase gene region longitudinally using UDS in an HIV-1-infected child rapidly failing a raltegravir-based regimen. Methods Longitudinal plasma samples at baseline and weeks 4, 8, 13, 17 and 39 were obtained, as well as the mother's baseline plasma sample. Sanger sequencing and UDS were performed on the integrase gene using Roche 454 GS-Junior. A bioinformatic workflow was developed to identify the major DRMs, accessory mutations and the linkage between mutations. Results In Sanger sequencing and UDS, no MRV in the integrase gene was detected at baseline in either the mother or the child. The major DRM N155H conferring resistance to raltegravir and elvitegravir was detected in 4% of the sequences by week 4 using UDS, whereas it was not detected by Sanger sequencing. The double mutant E92Q + N155H, conferring resistance to the entire integrase inhibitor class, including dolutegravir, emerged at week 8 (16%) and became rapidly dominant (57% by week 13). At the last timepoint under raltegravir (week 17), Y143R emerged, leading to different resistance mutation patterns: single mutants N155H (47%) and Y143R (24%) and double mutants E92Q + N155H (13%), Y143R + N155H (2%) and E92Q + Y143R (2%). The polymorphic substitution M50I was preferentially selected on resistant variants, especially on E92Q + N155H variants. Conclusions This case study illustrates the usefulness of UDS in detecting early MRVs and determining the dynamics of selected HIV-1 variants in longitudinal analysis. |
| Databáze: | OpenAIRE |
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