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
| العنوان: | 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 |
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| المؤلفون: | Nathan Osman, Melissa Wares, Peter K. Quashie, Thibault Mesplède, Diane N. Singhroy, Said Hassounah, Mark A. Wainberg, Ying-Shan Han, Kaitlin Anstett |
| المصدر: | Journal of Antimicrobial Chemotherapy. 69:2733-2740 |
| بيانات النشر: | Oxford University Press (OUP), 2014. |
| سنة النشر: | 2014 |
| مصطلحات موضوعية: | Models, Molecular, Microbiology (medical), Pyridones, Virus Integration, Molecular Conformation, Integrase inhibitor, HIV Integrase, Microbial Sensitivity Tests, Biology, Virus Replication, medicine.disease_cause, Piperazines, Cell Line, chemistry.chemical_compound, Drug Resistance, Viral, Oxazines, medicine, Humans, Pharmacology (medical), HIV Integrase Inhibitors, Original Research, Pharmacology, Mutation, Elvitegravir, Raltegravir, Virology, Integrase, Enzyme Activation, Infectious Diseases, Amino Acid Substitution, chemistry, Viral replication, Dolutegravir, HIV-1, biology.protein, Heterocyclic Compounds, 3-Ring, HIV drug resistance, Protein Binding, medicine.drug |
| الوصف: | Background The results of several clinical trials suggest that the integrase inhibitor dolutegravir may be less prone than other drugs to the emergence of HIV drug resistance mutations in treatment-naive patients. We have shown that the R263K mutation commonly emerged during tissue culture selection studies with dolutegravir and conferred low levels of resistance to this drug while simultaneously diminishing both HIV replication capacity and integrase enzymatic activity. E138K has been identified as a secondary mutation for dolutegravir in selection studies and has also been observed as a secondary mutation in the clinic for the integrase inhibitors raltegravir and elvitegravir. Methods We used biochemical cell-free strand-transfer assays and tissue culture assays to characterize the effects of the E138K/R263K combination of mutations on resistance to dolutegravir, integrase enzyme activity and HIV-1 replication capacity. Results We show here that the addition of the E138K substitution to R263K increased the resistance of HIV-1 to dolutegravir but failed to restore viral replication capacity, integrase strand-transfer activity and integration within cellular DNA. We also show that the addition of E138K to R263K did not increase the resistance to raltegravir or elvitegravir. The addition of the E138K substitution to R263K was also less detrimental to integrase strand-transfer activity and integration than a different secondary mutation at position H51Y that had also been selected in culture. Conclusions The E138K substitution failed to restore the defect in viral replication capacity that is associated with R263K, confirming previous selection studies that failed to identify compensatory mutation(s) for the latter primary mutation. This study suggests that the R263K resistance pathway may represent an evolutionary dead end for HIV in treatment-naive individuals who are treated with dolutegravir and will need to be confirmed by the long-term use of dolutegravir in the clinic. |
| تدمد: | 1460-2091 0305-7453 |
| DOI: | 10.1093/jac/dku199 |
| URL الوصول: | https://explore.openaire.eu/search/publication?articleId=doi_dedup___::9d35b5aac86c575a1b80c90d8f670fc2 https://doi.org/10.1093/jac/dku199 |
| Rights: | OPEN |
| رقم الانضمام: | edsair.doi.dedup.....9d35b5aac86c575a1b80c90d8f670fc2 |
| قاعدة البيانات: | OpenAIRE |
| تدمد: | 14602091 03057453 |
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| DOI: | 10.1093/jac/dku199 |