Mutations Located outside the Integrase Gene Can Confer Resistance to HIV-1 Integrase Strand Transfer Inhibitors - CNRS - Centre national de la recherche scientifique Accéder directement au contenu
Article Dans Une Revue mBio Année : 2017

Mutations Located outside the Integrase Gene Can Confer Resistance to HIV-1 Integrase Strand Transfer Inhibitors

Résumé

Resistance to the integrase strand transfer inhibitors raltegravir and elvitegravir is often due to well-identified mutations in the integrase gene. However, the situation is less clear for patients who fail dolutegravir treatment. Furthermore, most in vitro experiments to select resistance to dolutegravir have resulted in few mutations of the integrase gene. We performed an in vitro dolutegravir resistance selection experiment by using a breakthrough method. First, MT4 cells were infected with human immunodeficiency virus type 1 (HIV-1) Lai. After integration into the host cell genome, cells were washed to remove unbound virus and 500 nM dolutegravir was added to the cell medium. This high concentration of the drug was maintained throughout selection. At day 80, we detected a virus highly resistant to dolutegravir, raltegravir, and elvitegravir that remained susceptible to zidovudine. Sequencing of the virus showed no mutations in the integrase gene but highlighted the emergence of five mutations, all located in the nef region, of which four were clustered in the 3′ polypurine tract (PPT). Mutations selected in vitro by dolutegravir, located outside the integrase gene, can confer a high level of resistance to all integrase inhibitors. Thus, HIV-1 can use an alternative mechanism to develop resistance to integrase inhibitors by selecting mutations in the 3′ PPT region. Further studies are required to determine to what extent these mutations may explain virological failure during integrase inhibitor therapy.

Domaines

Virologie
Fichier principal
Vignette du fichier
isabelle Malet MBio.pdf (1.76 Mo) Télécharger le fichier
Origine : Fichiers éditeurs autorisés sur une archive ouverte
Loading...

Dates et versions

hal-01680815 , version 1 (11-01-2018)

Identifiants

Citer

Isabelle Malet, Frédéric Subra, Charlotte Charpentier, Gilles Collin, Diane Descamps, et al.. Mutations Located outside the Integrase Gene Can Confer Resistance to HIV-1 Integrase Strand Transfer Inhibitors. mBio, 2017, 8 (5), pp.e00922-17. ⟨10.1128/mBio.00922-17⟩. ⟨hal-01680815⟩
266 Consultations
117 Téléchargements

Altmetric

Partager

Gmail Facebook X LinkedIn More