Pathway involving the N155H mutation in HIV-1 integrase leads to dolutegravir resistance.
J Antimicrob Chemother
; 73(5): 1158-1166, 2018 05 01.
Article
em En
| MEDLINE
| ID: mdl-29373677
ABSTRACT
Background:
Dolutegravir, an integrase strand-transfer inhibitor (STI), shows a high genetic barrier to resistance. Dolutegravir is reported to be effective against viruses resistant to raltegravir and elvitegravir. In this study, we report the case of a patient treated with dolutegravir monotherapy. Failure of dolutegravir treatment was observed concomitant with the appearance of N155H-K211R-E212T mutations in the integrase (IN) gene in addition to the polymorphic K156N mutation that was present at baseline in this patient.Methods:
The impact of N155H-K156N-K211R-E212T mutations was studied in cell-free, culture-based assays and by molecular modelling.Results:
Cell-free and culture-based assays confirm that selected mutations in the patient, in the context of the polymorphic mutation K156N present at the baseline, lead to high resistance to dolutegravir requiring that the analysis be done at timepoints longer than usual to properly reveal the results. Interestingly, the association of only N155H and K156N is sufficient for significant resistance to dolutegravir. Modelling studies showed that dolutegravir is less stable in IN/DNA complexes with respect to the WT sequence.Conclusions:
Our results indicate that the stability of STI IN/DNA complexes is an important parameter that must be taken into account when evaluating dolutegravir resistance. This study confirms that a pathway including N155H can be selected in patients treated with dolutegravir with the help of the polymorphic K156N that acts as a secondary mutation that enhances the resistance to dolutegravir.
Texto completo:
1
Coleções:
01-internacional
Base de dados:
MEDLINE
Assunto principal:
HIV-1
/
Inibidores de Integrase de HIV
/
Integrase de HIV
/
Mutação de Sentido Incorreto
/
Farmacorresistência Viral
/
Compostos Heterocíclicos com 3 Anéis
Tipo de estudo:
Prognostic_studies
Limite:
Humans
Idioma:
En
Revista:
J Antimicrob Chemother
Ano de publicação:
2018
Tipo de documento:
Article
País de afiliação:
França