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

Journal of Antimicrobial Chemotherapy

Volumn 69, Issue 10, 2014, Pages 2733-2740

  Mesplède, Thibault ^a   Osman, Nathan ^a,b   Wares, Melissa ^a,b   Quashie, Peter K ^a,c   Hassounah, Said ^a,c   Anstett, Kaitlin ^a,b   Han, Yingshan ^a   Singhroy, Diane N ^a,b   Wainberg, Mark A ^a,b,c  

^a MCGILL UNIVERSITY   (Canada)

^b MCGILL UNIVERSITY   (Canada)

^c MCGILL UNIVERSITY   (Canada)

Author keywords

Antiviral; HIV 1; Integrase inhibitors

Indexed keywords

CELL DNA; DOLUTEGRAVIR; ELVITEGRAVIR; INTEGRASE; RALTEGRAVIR; VIRUS DNA; FUSED HETEROCYCLIC RINGS; INTEGRASE INHIBITOR; PROTEIN BINDING;

ARTICLE; ENZYME ACTIVITY; HUMAN; HUMAN CELL; HUMAN IMMUNODEFICIENCY VIRUS 1; MUTATION; NONHUMAN; VIRUS CELL INTERACTION; VIRUS INFECTIVITY; VIRUS REPLICATION; VIRUS RESISTANCE; AMINO ACID SUBSTITUTION; ANTIVIRAL RESISTANCE; CELL LINE; CHEMICAL STRUCTURE; CHEMISTRY; CONFORMATION; DRUG EFFECTS; ENZYME ACTIVATION; GENETICS; METABOLISM; MICROBIAL SENSITIVITY TEST; VIRUS DNA CELL DNA INTERACTION;

AMINO ACID SUBSTITUTION; CELL LINE; DRUG RESISTANCE, VIRAL; ENZYME ACTIVATION; HETEROCYCLIC COMPOUNDS, 3-RING; HIV INTEGRASE; HIV INTEGRASE INHIBITORS; HIV-1; HUMANS; MICROBIAL SENSITIVITY TESTS; MODELS, MOLECULAR; MOLECULAR CONFORMATION; MUTATION; PROTEIN BINDING; VIRUS INTEGRATION; VIRUS REPLICATION;

EID: 84908253044     PISSN: 03057453     EISSN: 14602091     Source Type: Journal    
DOI: 10.1093/jac/dku199     Document Type: Article

References (40)

1. Wainberg MA, Zaharatos GJ, Brenner BG. Development of antiretroviral drug resistance. N Engl J Med 2011; 365: 637-46.
2. Wainberg MA, Mesplede T, Raffi F. What if HIV were unable to develop resistance against a new therapeutic agent? BMC Med 2013; 11: 249.
3. Mesplede T,Wainberg M. Integrase strand transfer inhibitors in HIV therapy. Infec Dis and Therapy 2013; 2: 83-93.
4. Eron JJ, Clotet B, Durant J et al. Safety and efficacy of dolutegravir in treatment-experienced subjects with raltegravir-resistant HIV type 1 infection: 24-week results of the VIKING study. J Infect Dis 2013; 207: 740-8.
5. Castagna A, Maggiolo F, Penco G et al. Dolutegravir in antiretroviralexperienced patients with raltegravir-and/or elvitegravir-resistant HIV-1: 24-week results of the Phase III VIKING-3 study. J Infect Dis 2014; doi:10.1093/infdis/jiu051.
6. Quashie PK, Mesplede T, Han YS et al. Characterization of the R263K mutation in HIV-1 integrase that confers low-level resistance to the second-generation integrase strand transfer inhibitor dolutegravir. J Virol 2012; 86: 2696-705.
7. Cahn P, Pozniak AL, Mingrone H et al. Dolutegravir versus raltegravir in antiretroviral-experienced, integrase-inhibitor-naive adults with HIV: week 48 results from the randomised, double-blind, non-inferiority SAILING study. Lancet 2013; 382: 700-8.
8. Mesplede T, Quashie PK, Osman N et al. Viral fitness cost prevents HIV-1 from evading dolutegravir drug pressure. Retrovirology 2013; 10: 22.
9. Wares M, Mesplede T, Quashie PK et al. 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 2014; 11: 7.
10. Oliveira M, Mesplede T, Quashie PK et al. Resistance mutations against dolutegravir in HIV integrase impair the emergence of resistance against reverse transcriptase inhibitors. Aids 2014; 28: 813-9.
11. Bar-Magen T, Sloan RD, Donahue DA et al. Identification of novel mutations responsible for resistance to MK-2048, a second-generation HIV-1 integrase inhibitor. J Virol 2010; 84: 9210-6.
12. Shimura K, Kodama E, Sakagami Y et al. Broad antiretroviral activity and resistance profile of the novel human immunodeficiency virus integrase inhibitor elvitegravir (JTK-303/GS-9137). J Virol 2008; 82: 764-74.
13. Blanco JL, Varghese V, Rhee SY et al. HIV-1 integrase inhibitor resistance and its clinical implications. J Infect Dis 2011; 203: 1204-14.
14. Seki T, Kobayashi M, Wakasa-Morimoto C et al. S/GSK1349572 is a potent next generation HIV integrase inhibitor and demonstrates a superior resistance profile substantiated with 60 integrase mutant molecular clones. In: Abstracts of the Seventeenth Conference on Retroviruses and Opportunistic Infections, San Francisco, CA, 2010. Abstract 555. Foundation for Retrovirology and Human Health, Alexandria, VA, USA.
15. Kobayashi M, Yoshinaga T, Seki T et al. In vitro antiretroviral properties of S/GSK1349572, a next-generation HIV integrase inhibitor. Antimicrob Agents Chemother 2011; 55: 813-21.
16. Quashie PK, Mesplede T, Han YS et al. Biochemical analysis of the role of G118R-linked dolutegravir drug resistance substitutions in HIV-1 integrase. Antimicrob Agents Chemother 2013; 57: 6223-35.
17. Yu JJ, Wu TL, Liszewski MK et al. A more precise HIV integration assay designed to detect small differences finds lower levels of integrated DNA in HAART treated patients. Virology 2008; 379: 78-86.
18. The PyMol Molecular Graphics System, Version 1.3. Schrodinger, LLC.
19. Krieger E, Koraimann G, Vriend G. Increasing the precision of comparative models with YASARA NOVA-a self-parameterizing force field. Proteins 2002; 47: 393-402.
20. Dewar MJ. Some recent developments in quantum organic chemistry. Ciba Found Symp 1978; 107-29.
21. Canutescu AA, Dunbrack RL Jr. Cyclic coordinate descent: a robotics algorithm for protein loop closure. Protein Sci 2003; 12: 963-72.
22. Quashie PK, Mesplede T, Han YS et al. Erratum: Biochemical analysis of the role of G118R-linked dolutegravir drug resistance substitutions in HIV-1 integrase. Antimicrob Agents Chemother 2014; 58: 633.
23. Raffi F, Jaeger H, Quiros-Roldan E et al. Once-daily dolutegravir versus twice-daily raltegravir in antiretroviral-naive adults with HIV-1 infection (SPRING-2 study): 96 week results from a randomised, double-blind, noninferiority trial. Lancet Infect Dis 2013; 13: 927-35.
24. Raffi F, Rachlis A, Stellbrink HJ et al. Once-daily dolutegravir versus raltegravir in antiretroviral-naive adults with HIV-1 infection: 48 week results from the randomised, double-blind, non-inferiority SPRING-2 study. Lancet 2013; 381: 735-43.
25. van Lunzen J, Maggiolo F, Arribas JR et al. Once daily dolutegravir (S/GSK1349572) in combination therapy in antiretroviral-naive adults with HIV: planned interim 48 week results from SPRING-1, a dose-ranging, randomised, phase 2b trial. Lancet Infect Dis 2012; 12: 111-8.
26. Walmsley SL, Antela A, Clumeck N et al. Dolutegravir plus abacavirlamivudine for the treatment of HIV-1 infection. N Engl J Med 2013; 369: 1807-18.
27. Eron JJ Jr., Rockstroh JK, Reynes J et al. Raltegravir once daily or twice daily in previously untreated patients with HIV-1: a randomised, activecontrolled, phase 3 non-inferiority trial. Lancet Infect Dis 2011; 11: 907-15.
28. Lennox JL, Dejesus E, Berger DS et al. Raltegravir versus efavirenz regimens in treatment-naive HIV-1-infected patients: 96-week efficacy, durability, subgroup, safety, and metabolic analyses. J Acquir Immune Defic Syndr 2010; 55: 39-48.
29. Lennox JL, DeJesus E, Lazzarin A et al. Safety and efficacy of raltegravirbased versus efavirenz-based combination therapy in treatment-naive patients with HIV-1 infection: a multicentre, double-blind randomised controlled trial. Lancet 2009; 374: 796-806.
30. Markowitz M, Nguyen BY, Gotuzzo E et al. Sustained antiretroviral effect of raltegravir after 96 weeks of combination therapy in treatment-naive patients with HIV-1 infection. J Acquir Immune Defic Syndr 2009; 52: 350-6.
31. Markowitz M, Nguyen BY, Gotuzzo E et al. Rapid and durable antiretroviral effect of the HIV-1 Integrase inhibitor raltegravir as part of combination therapy in treatment-naive patients with HIV-1 infection: results of a 48-week controlled study. J Acquir Immune Defic Syndr 2007; 46: 125-33.
32. Reynes J, Lawal A, Pulido F et al. Examination of noninferiority, safety, and tolerability of lopinavir/ritonavir and raltegravir compared with lopinavir/ritonavir and tenofovir/emtricitabine in antiretroviral-naive subjects: the progress study, 48-week results. HIV Clin Trials 2011; 12: 255-67.
33. Reynes J, Trinh R, Pulido F et al. Lopinavir/ritonavir combined with raltegravir or tenofovir/emtricitabine in antiretroviral-naive subjects: 96-week results of the PROGRESS study. AIDS Res Hum Retroviruses 2013; 29: 256-65.
34. Rockstroh JK, DeJesus E, Lennox JL et al. Durable efficacy and safety of raltegravir versus efavirenz when combined with tenofovir/emtricitabine in treatment-naive HIV-1-infected patients: final 5-year results from STARTMRK. J Acquir Immune Defic Syndr 2013; 63: 77-85.
35. DeJesus E, Rockstroh JK, Henry K et al. Co-formulated elvitegravir, cobicistat, emtricitabine, and tenofovir disoproxil fumarate versus ritonavirboosted atazanavir plus co-formulated emtricitabine and tenofovir disoproxil fumarate for initial treatment of HIV-1 infection: a randomised, double-blind, phase 3, non-inferiority trial. Lancet 2012; 379: 2429-38.
36. Rockstroh JK, DeJesus E, Henry K et al. A randomized, double-blind comparison of coformulated elvitegravir/cobicistat/emtricitabine/tenofovir DF vs ritonavir-boosted atazanavir plus coformulated emtricitabine and tenofovir DF for initial treatment of HIV-1 infection: analysis of week 96. results. J Acquir Immune Defic Syndr 2013; 62: 483-6.
37. Sax PE, DeJesus E, Mills A et al. Co-formulated elvitegravir, cobicistat, emtricitabine, and tenofovir versus co-formulated efavirenz, emtricitabine, and tenofovir for initial treatment of HIV-1 infection: a randomised, double-blind, phase 3 trial, analysis of results after 48 weeks. Lancet 2012; 379: 2439-48.
38. Zolopa A, Sax PE, DeJesus E et al. A randomized double-blind comparison of coformulated elvitegravir/cobicistat/emtricitabine/tenofovir disoproxil fumarate versus efavirenz/emtricitabine/tenofovir disoproxil fumarate for initial treatment of HIV-1 infection: analysis of week 96 results. J Acquir Immune Defic Syndr 2013; 63: 96-100.
39. Greenwald J, Le V, Butler SL et al. The mobility of an HIV-1 integrase active site loop is correlated with catalytic activity. Biochemistry 1999; 38: 8892-8.
40. Hare S, Smith SJ, Metifiot M et al. Structural and functional analyses of the second-generation integrase strand transfer inhibitor dolutegravir (S/GSK1349572). Mol Pharmacol 2011; 80: 565-72.