Variability of the HIV-1 3' polypurine tract (3'PPT) region and implication in integrase inhibitor resistance.
Base Sequence
Drug Resistance, Viral
/ genetics
Genotype
HIV Infections
/ drug therapy
HIV Integrase
/ genetics
HIV Integrase Inhibitors
/ pharmacology
HIV-1
/ drug effects
Humans
Mutation
Purines
Retrospective Studies
Reverse Transcription
Sequence Analysis, DNA
Treatment Failure
Viral Proteins
/ genetics
Virus Replication
/ drug effects
Journal
The Journal of antimicrobial chemotherapy
ISSN: 1460-2091
Titre abrégé: J Antimicrob Chemother
Pays: England
ID NLM: 7513617
Informations de publication
Date de publication:
01 12 2019
01 12 2019
Historique:
received:
07
05
2019
revised:
16
07
2019
accepted:
01
08
2019
entrez:
16
11
2019
pubmed:
16
11
2019
medline:
26
9
2020
Statut:
ppublish
Résumé
Integrase strand-transfer inhibitors (INSTIs) are efficient at impairing retroviral integration, which is a critical step in HIV-1 replication. To date, resistance to these compounds has been explained by mutations in the viral protein integrase, which catalyses the integration step. Recently, it has been shown that selected mutations in the 3' polypurine tract (3'PPT), a sequence involved in the reverse transcription mechanism, result in high-level resistance to these compounds. This observation was reinforced by the description of a patient who failed INSTI treatment by selecting mutations in the 3'PPT sequence. Sequences of the 3'PPT region were analysed in 30706 treatment-naive patients from the public Los Alamos database belonging to six different subtypes and, in parallel, in 107 patients failing INSTI treatment. The analysis showed that the sequences of patients failing INSTI treatment, in the same way as those of treatment-naive patients, are very well conserved regardless of the presence or absence of resistance mutations in the integrase gene. This study confirms that the selection of a mutation in the 3'PPT region conferring high-level resistance to INSTIs is a rare event. It would require a particular in vivo context and especially a long enough time to be selected, this exposure time being generally reduced by the rapid change of treatment in the case of virological failure. Larger-scale studies in patients with INSTI treatment failure are needed to determine whether the 3'PPT region can play an important role in vivo in INSTI resistance.
Sections du résumé
BACKGROUND
Integrase strand-transfer inhibitors (INSTIs) are efficient at impairing retroviral integration, which is a critical step in HIV-1 replication. To date, resistance to these compounds has been explained by mutations in the viral protein integrase, which catalyses the integration step. Recently, it has been shown that selected mutations in the 3' polypurine tract (3'PPT), a sequence involved in the reverse transcription mechanism, result in high-level resistance to these compounds. This observation was reinforced by the description of a patient who failed INSTI treatment by selecting mutations in the 3'PPT sequence.
METHODS
Sequences of the 3'PPT region were analysed in 30706 treatment-naive patients from the public Los Alamos database belonging to six different subtypes and, in parallel, in 107 patients failing INSTI treatment.
RESULTS
The analysis showed that the sequences of patients failing INSTI treatment, in the same way as those of treatment-naive patients, are very well conserved regardless of the presence or absence of resistance mutations in the integrase gene.
CONCLUSIONS
This study confirms that the selection of a mutation in the 3'PPT region conferring high-level resistance to INSTIs is a rare event. It would require a particular in vivo context and especially a long enough time to be selected, this exposure time being generally reduced by the rapid change of treatment in the case of virological failure. Larger-scale studies in patients with INSTI treatment failure are needed to determine whether the 3'PPT region can play an important role in vivo in INSTI resistance.
Identifiants
pubmed: 31730161
pii: 5561473
doi: 10.1093/jac/dkz377
doi:
Substances chimiques
HIV Integrase Inhibitors
0
Purines
0
Viral Proteins
0
HIV Integrase
EC 2.7.7.-
Types de publication
Journal Article
Research Support, Non-U.S. Gov't
Langues
eng
Sous-ensembles de citation
IM
Pagination
3440-3444Informations de copyright
© The Author(s) 2019. Published by Oxford University Press on behalf of the British Society for Antimicrobial Chemotherapy. All rights reserved. For permissions, please email: journals.permissions@oup.com.