Abstract
BackgroundFirst-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.ResultsUsing 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.ConclusionsSince 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.
Highlights
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
Our results demonstrate that the M50I polymorphism does not restore the loss in HIV-1 infectivity associated with R263K and confers moderate resistance to DTG when combined with the latter resistance mutation
We wanted to determine the frequency with which the M50I polymorphism occurs in the INSTI-naïve patient population
Summary
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. Their relatively low genetic barrier for resistance makes them susceptible to the emergence of drug resistance mutations. HIV-1 integrase (IN) is a protein comprising 288 amino acids structured into three domains, i.e. the Nterminal domain, the catalytic core domain and the Cterminal domain [4] These domains are critical for the proper function of HIV-1 integrase, which is to catalyze the insertion of the proviral DNA into the host chromosome.
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