Polymorphic substitution E157Q in HIV-1 integrase increases R263K-mediated dolutegravir resistance and decreases DNA binding activity

Journal of Antimicrobial Chemotherapy

Volumn 71, Issue 8, 2016, Pages 2083-2088

  Anstett, Kaitlin ^a,b   Cutillas, Vincent ^a,b   Fusco, Robert ^a,c   Mesplède, Thibault ^a   Wainberg, Mark A ^a,b  

^a MCGILL UNIVERSITY   (Canada)

^b MCGILL UNIVERSITY   (Canada)

^c Enanta Pharmaceuticals Inc   (United States)

Author keywords

[No Author keywords available]

Indexed keywords

ANTI HUMAN IMMUNODEFICIENCY VIRUS AGENT; DOLUTEGRAVIR; FZ 41; INTEGRASE; INTEGRASE INHIBITOR; RALTEGRAVIR; UNCLASSIFIED DRUG; VIRUS DNA; DNA; FUSED HETEROCYCLIC RINGS; MUTANT PROTEIN; P31 INTEGRASE PROTEIN, HUMAN IMMUNODEFICIENCY VIRUS 1; PROTEIN BINDING; RECOMBINANT PROTEIN;

ANTIVIRAL RESISTANCE; ANTIVIRAL SUSCEPTIBILITY; ARTICLE; BINDING AFFINITY; CELL FREE SYSTEM; CONTROLLED STUDY; DNA POLYMORPHISM; DNA STRAND; DNA TRANSFER; DRUG BINDING SITE; ENZYME ACTIVITY; GENETIC ASSOCIATION; GENETIC BACKGROUND; HUMAN IMMUNODEFICIENCY VIRUS 1 (STRAIN NL4.3); NONHUMAN; PROTEIN DNA BINDING; TISSUE CULTURE; VIRUS INFECTIVITY; VIRUS MUTANT; VIRUS MUTATION; AMINO ACID SUBSTITUTION; DRUG EFFECTS; ENZYMOLOGY; GENETICS; HUMAN; HUMAN IMMUNODEFICIENCY VIRUS 1; ISOLATION AND PURIFICATION; METABOLISM; MISSENSE MUTATION;

AMINO ACID SUBSTITUTION; DNA; DRUG RESISTANCE, VIRAL; HETEROCYCLIC COMPOUNDS, 3-RING; HIV INTEGRASE; HIV INTEGRASE INHIBITORS; HIV-1; HUMANS; MUTANT PROTEINS; MUTATION, MISSENSE; PROTEIN BINDING; RECOMBINANT PROTEINS;

EID: 84982224092     PISSN: 03057453     EISSN: 14602091     Source Type: Journal    
DOI: 10.1093/jac/dkw109     Document Type: Article

References (26)

1. Lauring AS, Andino R. Quasispecies theory and the behavior of RNA viruses. PLoS Pathog 2010; 6: e1001005.
2. Roberts JD, Bebenek K, Kunkel TA. The accuracy of reverse transcriptase from HIV-1. Science 1988; 242: 1171-3.
3. WHO. WHO HIV Drug Resistance Report 2012. http://www.who.int/hiv/ pub/drugresistance/report2012/en/index.html.
4. 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.
5. Mesplede T, Quashie PK, Zanichelli V et al. Integrase strand transfer inhibitors in the management of HIV-positive individuals. Ann Med 2014; 46: 123-9.
6. Blanco JL, Varghese V, Rhee SY et al. HIV-1 integrase inhibitor resistance and its clinical implications. J Infect Dis 2011; 203: 1204-14.
7. Shafer RW. Rationale and uses of a public HIV drug-resistance database. J Infect Dis 2006; 194 Suppl 1: S51-8.
8. 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.
9. 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.
10. Mesplede T, Quashie PK, Osman N et al. Viral fitness cost prevents HIV-1 from evading dolutegravir drug pressure. Retrovirology 2013; 10: 22.
11. Danion F, Belissa E, Peytavin G et al. Non-virological response to a dolutegravir-containing regimen in a patient harbouring a E157Q-mutated virus in the integrase region. J Antimicrob Chemother 2015; 70: 1921-3.
12. Lataillade M, Chiarella J, Kozal MJ. Natural polymorphism of the HIV-1 integrase gene and mutations associated with integrase inhibitor resistance. Antivir Ther 2007; 12: 563-70.
13. Anstett K, Fusco R, Cutillas V et al. Dolutegravir-selected HIV-1 containing the N155H and R263K resistance substitutions does not acquire additional compensatory mutations under drug pressure that lead to higher-level resistance and increased replicative capacity. J Virol 2015; 89: 10482-8.
14. Quashie PK, Han YS, Hassounah S et al. Structural studies of the HIV-1 integrase protein: compound screening and characterization of a DNA-binding inhibitor. PLoS One 2015; 10: e0128310.
15. Cutillas V, Mesplede T, Anstett K et al. The R262K substitution combined with H51Y in HIV-1 subtype B integrase confers low-level resistance against dolutegravir. Antimicrob Agents Chemother 2015; 59: 310-6.
16. Han YS, Xiao WL, Quashie PK et al. Development of a fluorescencebased HIV-1 integrase DNA binding assay for identification of novel HIV-1 integrase inhibitors. Antiviral Res 2013; 98: 441-8.
17. 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.
18. Mesplede T, Osman N, Wares M et al. 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. J Antimicrob Chemother 2014; 69: 2733-40.
19. Anstett K, Mesplede T, Oliveira M et al. Dolutegravir resistance mutation R263K cannot coexist in combination with many classical integrase inhibitor resistance substitutions. J Virol 2015; 89: 4681-4.
20. Berg JM, Tymoczko JL, Stryer L. The Michaelis-Menten model accounts for the kinetic properties of many enzymes. Section 8.4. In: Biochemistry. New York: W. H. Freeman, 2002.
21. Ghosn J, Mazet AA, Avettand-Fenoel V et al. Rapid selection and archiving of mutation E157Q in HIV-1 DNA during short-term low-level replication on a raltegravir-containing regimen. J Antimicrob Chemother 2009; 64: 433-4.
22. 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; 210: 354-62.
23. Hurt CB, Sebastian J, Hicks CB et al. Resistance to HIV integrase strand transfer inhibitors among clinical specimens in the United States, 2009-2012. Clin Infect Dis 2014; 58: 423-31.
24. Malet I, Soulie C, Tchertanov L et al. Structural effects of amino acid variations between B and CRF02-AG HIV-1 integrases. J Med Virol 2008; 80: 754-61.
25. Wainberg MA, Mesplede T. Implications for the future of the HIV epidemic if drug resistance against dolutegravir cannot occur in first-line therapy. J Int AIDS Soc 2015; 18: 20824.
26. Ceccherini-Silberstein F, Malet I, D'Arrigo R et al. Characterization and structural analysis of HIV-1 integrase conservation. AIDS Rev 2009; 11: 17-29.