Addition of E138K to R263K in HIV integrase increases resistance to dolutegravir, but fails to restore activity of the HIV integrase enzyme and viral replication capacity

摘要: Background The results of several clinical trials suggest that the integrase inhibitor dolutegravir may be less prone than other drugs to emergence HIV drug resistance mutations in treatment-naive patients. We have shown R263K mutation commonly emerged during tissue culture selection studies with and conferred low levels this while simultaneously diminishing both replication capacity enzymatic activity. E138K has been identified as a secondary for also observed clinic inhibitors raltegravir elvitegravir. Methods used biochemical cell-free strand-transfer assays characterize effects E138K/R263K combination on dolutegravir, enzyme activity HIV-1 capacity. Results show here addition substitution increased but failed restore viral capacity, integration within cellular DNA. did not increase or was detrimental different at position H51Y had selected culture. Conclusions defect is associated R263K, confirming previous identify compensatory mutation(s) latter primary mutation. This study suggests pathway represent an evolutionary dead end individuals who are treated will need confirmed by long-term use clinic.