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The M50I polymorphic substitution in association with the R263K mutation in HIV-1 subtype B integrase increases drug resistance but does not restore viral replicative fitness

Melissa Wares12, Thibault Mesplède1, Peter K Quashie13, Nathan Osman12, Yingshan Han1 and Mark A Wainberg123*

Author Affiliations

1 Lady Davis Institute for Medical Research, McGill University AIDS Centre, Jewish General Hospital, Montreal, Quebec, Canada

2 Department of Microbiology and Immunology, Faculty of Medicine, McGill University, Montreal, Quebec, Canada

3 Division of Experimental Medicine, Faculty of Medicine, McGill University, Montreal, Quebec, Canada

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Retrovirology 2014, 11:7  doi:10.1186/1742-4690-11-7

Published: 17 January 2014

Abstract

Background

First-generation integrase strand-transfer inhibitors (INSTIs), such as raltegravir (RAL) and elvitegravir (EVG), have been clinically proven to be effective antiretrovirals for the treatment of HIV-positive patients. However, their relatively low genetic barrier for resistance makes them susceptible to the emergence of drug resistance mutations. In contrast, dolutegravir (DTG) is a newer INSTI that appears to have a high genetic barrier to resistance in vivo. However, the emergence of the resistance mutation R263K followed by the polymorphic substitution M50I has been observed in cell culture. The M50I polymorphism is also observed in 10-25% of INSTI-naïve patients and has been reported in combination with R263K in a patient failing treatment with RAL.

Results

Using biochemical cell-free strand-transfer assays and resistance assays in TZM-bl cells, we demonstrate that the M50I polymorphism in combination with R263K increases resistance to DTG in tissue culture and in biochemical assays but does not restore the viral fitness cost associated with the R263K mutation.

Conclusions

Since the combination of the R263K mutation and the M50I polymorphism results in a virus with decreased viral fitness and limited cross-resistance, the R263K resistance pathway may represent an evolutionary dead-end. Although this hypothesis has not yet been proven, it may be more advantageous to treat HIV-positive individuals with DTG in first-line than in second or third-line therapy.

Keywords:
HIV integrase; Subtype B; Antiretrovirals; R263K; Resistance mutation; M50I; Polymorphism; INSTI-naïve