Isabelle Hardy1, Bluma Brenner2, Peter Quashie2, Réjean Thomas3, Christos Petropoulos4, Wei Huang4, Daniela Moisi2, Mark A Wainberg2, Michel Roger5. 1. Centre hospitalier de l'Université de Montréal (CHUM), Montréal, Québec, Canada. 2. McGill AIDS Center, Lady Davis Institute, Jewish General Hospital, McGill University, Montréal, Québec, Canada. 3. Clinique Médicale L'Actuel, Montréal, Québec, Canada. 4. Monogram Biosciences, South San Francisco, CA, USA. 5. Centre hospitalier de l'Université de Montréal (CHUM), Montréal, Québec, Canada Département de microbiologie, infectiologie et immunologie, Faculté de médecine, Université de Montréal, Montréal, Québec, Canada michel.roger.chum@ssss.gouv.qc.ca.
Abstract
OBJECTIVES: Dolutegravir has been recently approved for treatment-naive and -experienced HIV-infected subjects, including integrase inhibitor (INI)-experienced patients. Dolutegravir is a second-generation INI that can overcome many prior raltegravir and elvitegravir failures. Here, we report the evolution of resistance to dolutegravir in a highly treatment-experienced patient harbouring the major N155H mutation consequent to raltegravir treatment failure. METHODS: Genotypic and phenotypic analyses were done on longitudinal samples to determine viral resistance to INIs. Integrase amino acid sequence interactions with raltegravir and dolutegravir were assessed by molecular modelling and docking simulations. RESULTS: Five mutations (A49P, L68FL, T97A, E138K and L234V) were implicated in emergent dolutegravir resistance, with a concomitant severe compromise in viral replicative capacity. Molecular modelling and docking simulations revealed that dolutegravir binding to integrase was affected by these acquired dolutegravir mutations. CONCLUSIONS: Our findings identify a novel mutational pathway involving integrase mutations A49P and L234V, leading to dolutegravir resistance in a patient with the N155H raltegravir mutation.
OBJECTIVES:Dolutegravir has been recently approved for treatment-naive and -experienced HIV-infected subjects, including integrase inhibitor (INI)-experienced patients. Dolutegravir is a second-generation INI that can overcome many prior raltegravir and elvitegravir failures. Here, we report the evolution of resistance to dolutegravir in a highly treatment-experienced patient harbouring the major N155H mutation consequent to raltegravir treatment failure. METHODS: Genotypic and phenotypic analyses were done on longitudinal samples to determine viral resistance to INIs. Integrase amino acid sequence interactions with raltegravir and dolutegravir were assessed by molecular modelling and docking simulations. RESULTS: Five mutations (A49P, L68FL, T97A, E138K and L234V) were implicated in emergent dolutegravir resistance, with a concomitant severe compromise in viral replicative capacity. Molecular modelling and docking simulations revealed that dolutegravir binding to integrase was affected by these acquired dolutegravir mutations. CONCLUSIONS: Our findings identify a novel mutational pathway involving integrase mutations A49P and L234V, leading to dolutegravir resistance in a patient with the N155Hraltegravir mutation.
Authors: Bluma G Brenner; Réjean Thomas; José Luis Blanco; Ruxandra-Ilinca Ibanescu; Maureen Oliveira; Thibault Mesplède; Olga Golubkov; Michel Roger; Federico Garcia; Esteban Martinez; Mark A Wainberg Journal: J Antimicrob Chemother Date: 2016-03-29 Impact factor: 5.790
Authors: Robert A Smith; Dana N Raugi; Charlotte Pan; Papa Salif Sow; Moussa Seydi; James I Mullins; Geoffrey S Gottlieb Journal: Retrovirology Date: 2015-02-05 Impact factor: 4.602
Authors: Michael E Abram; Renee R Ram; Nicolas A Margot; Tiffany L Barnes; Kirsten L White; Christian Callebaut; Michael D Miller Journal: PLoS One Date: 2017-02-17 Impact factor: 3.240