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

Retrovirology

Mark A Wainberg²  Yingshan Han³  Nathan Osman¹  Peter K Quashie²  Thibault Mesplède³  Melissa Wares¹ 

[1] Department of Microbiology and Immunology, Faculty of Medicine, McGill University, Montreal, Quebec, Canada;Division of Experimental Medicine, Faculty of Medicine, McGill University, Montreal, Quebec, Canada;Lady Davis Institute for Medical Research, McGill University AIDS Centre, Jewish General Hospital, Montreal, Quebec, Canada

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

Others  :  804148
DOI  :  10.1186/1742-4690-11-7

 received in 2013-12-13, accepted in 2014-01-11,  发布年份 2014

【 摘 要 】

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.

【 授权许可】

   
2014 Wares et al.; licensee BioMed Central Ltd.

【 图 表 】

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