Multiple genetic pathways involving amino acid position 143 of HIV-1 integrase are preferentially associated with specific secondary amino acid substitutions and confer resistance to raltegravir and cross-resistance to elvitegravir

Antimicrobial Agents and Chemotherapy

Volumn 57, Issue 9, 2013, Pages 4105-4113

  Huang, Wei ^a   Frantzell, Arne ^a   Fransen, Signe ^a   Petropoulos, Christos J ^a  

^a MONOGRAM BIOSCIENCES   (United States)

Author keywords

[No Author keywords available]

Indexed keywords

ELVITEGRAVIR; INTEGRASE; RALTEGRAVIR;

AMINO ACID SEQUENCE; AMINO ACID SUBSTITUTION; ARTICLE; CROSS RESISTANCE; HUMAN; HUMAN IMMUNODEFICIENCY VIRUS; HUMAN IMMUNODEFICIENCY VIRUS PREVALENCE; OBSERVATIONAL STUDY; POPULATION; PRIORITY JOURNAL;

AMINO ACID SUBSTITUTION; DRUG RESISTANCE, VIRAL; GENES, REPORTER; HEK293 CELLS; HIV INFECTIONS; HIV INTEGRASE; HIV INTEGRASE INHIBITORS; HIV-1; HUMANS; LUCIFERASES; MUTAGENESIS, SITE-DIRECTED; PYRROLIDINONES; QUINOLONES; TYROSINE;

EID: 84882353303     PISSN: 00664804     EISSN: 10986596     Source Type: Journal    
DOI: 10.1128/AAC.00204-13     Document Type: Article

References (36)

1. Bonnenfant S, Thomas CM, Vita C, Subra F, Deprez E, Zouhiri F, Desmaele D, D'Angelo J, Mouscadet JF, Leh H. 2004. Styrylquinolines, integrase inhibitors acting prior to integration: a new mechanism of action for anti-integrase agents. J. Virol. 78:5728-5736.
2. Pannecouque C, Pluymers W, Van Maele B, Tetz V, Cherepanov P, De Clercq E, Witvrouw M, Debyser Z. 2002. New class of HIV integrase inhibitors that block viral replication in cell culture. Curr. Biol. 12:1169-1177.
3. Bushman FD, Craigie R. 1991. Activities of human immunodeficiency virus (HIV) integration protein in vitro: specific cleavage and integration of HIV DNA. Proc. Natl. Acad. Sci. U. S. A. 88:1339-1343.
4. Bushman FD, Fujiwara T, Craigie R. 1990. Retroviral DNA integration directed by HIV integration protein in vitro. Science 249:1555-1558.
5. Hazuda DJ, Felock P, Witmer M, Wolfe A, Stillmock K, Grobler JA, Espeseth A, Gabryelski L, Schleif W, Blau C, Miller MD. 2000. Inhibitors of strand transfer that prevent integration and inhibit HIV-1 replication in cells. Science 287:646-650.
6. Christ F, Debyser Z. 2013. The LEDGF/p75 integrase interaction, a novel target for anti-HIV therapy. Virology 435:102-109.
7. Grinsztejn B, Nguyen BY, Katlama C, Gatell JM, Lazzarin A, Vittecoq D, Gonzalez CJ, Chen J, Harvey CM, Isaacs RD. 2007. Safety and efficacy of the HIV-1 integrase inhibitor raltegravir (MK-0518) in treatmentexperienced patients with multidrug-resistant virus: a phase II randomised controlled trial. Lancet 369:1261-1269.
8. Cooper DA, Steigbigel RT, Gatell JM, Rockstroh JK, Katlama C, Yeni P, Lazzarin A, Clotet B, Kumar PN, Eron JE, Schechter M, Markowitz M, Loutfy MR, Lennox JL, Zhao J, Chen J, Ryan DM, Rhodes RR, Killar JA, Gilde LR, Strohmaier KM, Meibohm AR, Miller MD, Hazuda DJ, Nessly ML, DiNubile MJ, Isaacs RD, Teppler H, Nguyen BY. 2008. Subgroup and resistance analyses of raltegravir for resistant HIV-1 infection. N. Engl. J. Med. 359:355-365.
9. Steigbigel RT, Cooper DA, Kumar PN, Eron JE, Schechter M, Markowitz M, Loutfy MR, Lennox JL, Gatell JM, Rockstroh JK, Katlama C, Yeni P, Lazzarin A, Clotet B, Zhao J, Chen J, Ryan DM, Rhodes RR, Killar JA, Gilde LR, Strohmaier KM, Meibohm AR, Miller MD, Hazuda DJ, Nessly ML, DiNubile MJ, Isaacs RD, Nguyen BY, Teppler H. 2008. Raltegravir with optimized background therapy for resistant HIV-1 infection. N. Engl. J. Med. 359:339-354.
10. Hicks C, Gulick RM. 2009. Raltegravir: the first HIV type 1 integrase inhibitor. Clin. Infect. Dis. 48:931-939.
11. Lennox JL, Dejesus E, Berger DS, Lazzarin A, Pollard RB, Ramalho Madruga JV, Zhao J, Wan H, Gilbert CL, Teppler H, Rodgers AJ, Barnard RJ, Miller MD, Dinubile MJ, Nguyen BY, Leavitt R, Sklar P. 2010. 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. 55:39-48.
12. DeJesus E, Rockstroh JK, Henry K, Molina JM, Gathe J, Ramanathan S, Wei X, Yale K, Szwarcberg J, White K, Cheng AK, Kearney BP. 2012. Co-formulated elvitegravir, cobicistat, emtricitabine, and tenofovir disoproxil fumarate versus ritonavir-boosted 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 379:2429-2438.
13. Sax PE, DeJesus E, Mills A, Zolopa A, Cohen C, Wohl D, Gallant JE, Liu HC, Zhong L, Yale K, White K, Kearney BP, Szwarcberg J, Quirk E, Cheng AK. 2012. 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 379:2439-2448.
14. Walmsley S, Antela A, Clumeck N, Duiculescu D, Eberhard A, Gutierrez F, Hocqueloux L, Maggiolo F, Sandkovsky U, Granier C, Wynne B, Pappa K. 2012. Dolutegravir (DTG; S/GSK1349572)Abacavir/ lamivudine once daily statistically superior to tenofovir/emtricitabine/ efavirenz: 48-week results-SINGLE (ING114467). 52th Annu. Intersci. Conf. Antimicrob. Agents Chemother. (ICAAC) and the Infectious Diseases Society of America (IDSA) 46th Annu. Meet., San Francisco, CA.
15. Malet I, Delelis O, Valantin MA, Montes B, Soulie C, Wirden M, Tchertanov L, Peytavin G, Reynes J, Mouscadet JF, Katlama C, Calvez V, Marcelin AG. 2008. Mutations associated with failure of raltegravir treatment affect integrase sensitivity to the inhibitor in vitro. Antimicrob. Agents Chemother. 52:1351-1358.
16. Fransen S, Gupta S, Danovich R, Hazuda D, Miller M, Witmer M, Petropoulos CJ, Huang W. 2009. Loss of raltegravir susceptibility by human immunodeficiency virus type 1 is conferred via multiple nonoverlapping genetic pathways. J. Virol. 83:11440-11446.
17. Reigadas S, Anies G, Masquelier B, Calmels C, Stuyver LJ, Parissi V, Fleury H, Andreola ML. 2010. The HIV-1 integrase mutations Y143C/R are an alternative pathway for resistance to Raltegravir and impact the enzyme functions. PLoS One. 5:e10311. doi:10.1371/journal.pone.0010311.
18. Delelis O, Thierry S, Subra F, Simon F, Malet I, Alloui C, Sayon S, Calvez V, Deprez E, Marcelin AG, Tchertanov L, Mouscadet JF. 2010. Impact of Y143 HIV-1 integrase mutations on resistance to Raltegravir in vitro and in vivo. Antimicrob. Agents Chemother. 54:491-501.
19. Canducci F, Marinozzi MC, Sampaolo M, Boeri E, Spagnuolo V, Gianotti N, Castagna A, Paolucci S, Baldanti F, Lazzarin A, Clementi M. 2010. Genotypic/phenotypic patterns of HIV-1 integrase resistance to raltegravir. J. Antimicrob. Chemother. 65:425-433.
20. Goethals O, Clayton R, Van Ginderen M, Vereycken I, Wagemans E, Geluykens P, Dockx K, Strijbos R, Smits V, Vos A, Meersseman G, Jochmans D, Vermeire K, Schols D, Hallenberger S, Hertogs K. 2008. Resistance mutations in human immunodeficiency virus type 1 integrase selected with elvitegravir confer reduced susceptibility to a wide range of integrase inhibitors. J. Virol. 82:10366-10374.
21. Garrido C, Villacian J, Zahonero N, Pattery T, Garcia F, Gutierrez F, Caballero E, Van Houtte M, Soriano V, de Mendoza C. 2012. Broad phenotypic cross-resistance to elvitegravir in HIV-infected patients failing on raltegravir-containing regimens. Antimicrob. Agents Chemother. 56: 2873-2878.
22. Abram ME, Hluhanich RM, Goodman DD, Andreatta KN, Margot NA, Ye L, Nlidziela-Majka A, Barnes TL, Novikov N, Chen X, Svarovskaia ES, McColl DJ, White KL, Miller MD. 2013. Impact of primary elvitegravir resistance-associated mutations in HIV-1 integrase on drug susceptibility and viral replication fitness. Antimicrob. Agents Chemother. 57: 2654-2663.
23. Metifiot M, Vandegraaff N, Maddali K, Naumova A, Zhang X, Rhodes D, Marchand C, Pommier Y. 2011. Elvitegravir overcomes resistance to raltegravir induced by integrase mutation Y143. AIDS 25:1175-1178.
24. Malet I, Delelis O, Soulie C, Wirden M, Tchertanov L, Mottaz P, Peytavin G, Katlama C, Mouscadet JF, Calvez V, Marcelin AG. 2009. Quasispecies variant dynamics during emergence of resistance to raltegravir in HIV-1-infected patients. J. Antimicrob. Chemother. 63:795-804.
25. da Silva D, Van Wesenbeeck L, Breilh D, Reigadas S, Anies G, Van Baelen K, Morlat P, Neau D, Dupon M, Wittkop L, Fleury H, Masquelier B. 2010. HIV-1 resistance patterns to integrase inhibitors in antiretroviral-experienced patients with virological failure on raltegravircontaining regimens. J. Antimicrob. Chemother. 65:1262-1269.
26. Mukherjee R, Jensen ST, Male F, Bittinger K, Hodinka RL, Miller MD, Bushman FD. 2011. Switching between raltegravir resistance pathways analyzed by deep sequencing. AIDS 25:1951-1959.
27. Fransen S, Gupta S, Frantzell A, Petropoulos CJ, Huang W. 2012. Substitutions at amino acid positions 143, 148, and 155 of HIV-1 integrase define distinct genetic barriers to raltegravir resistance in vivo. J. Virol. 86:7249-7255.
28. Blanco JL, Varghese V, Rhee SY, Gatell JM, Shafer RW. 2011. HIV-1 integrase inhibitor resistance and its clinical implications. J. Infect. Dis. 203:1204-1214.
29. Delelis O, Malet I, Na L, Tchertanov L, Calvez V, Marcelin AG, Subra F, Deprez E, Mouscadet JF. 2009. The G140S mutation in HIV integrases from raltegravir-resistant patients rescues catalytic defect due to the resistance Q148H mutation. Nucleic Acids Res. 37:1193-1201.
30. Reigadas S, Masquelier B, Calmels C, Laguerre M, Lazaro E, Vandenhende M, Neau D, Fleury H, Andreola ML. 2011. Structure-analysis of the HIV-1 integrase Y143C/R raltegravir resistance mutation in association with the secondary mutation T97A. Antimicrob. Agents Chemother. 55:3187-3194.
31. Cooper D, Gatell JM, Rockstroh J, Katlama C, Yeni P, Lazzarin A, Chen J, Isaacs R, Teppler H, Nguyen B, Group Benchmark Study Team. 2007. Results of BENCHMRK-1, a phase III study evaluating the efficacy and safety of raltegravir (MK-0518), a novel HIV-integrase inhibitor, in patients with triple-class resistant virus, abstr. 105a LB. 14th Conf. Retrovir. Opportun. Infect., Los Angeles, CA.
32. Sarkar G, Sommer SS. 1990. The "megaprimer" method of site-directed mutagenesis. Biotechniques 8:404-407.
33. Winters MA, Lloyd RM, Jr, Shafer RW, Kozal MJ, Miller MD, Holodniy M. 2012. Development of elvitegravir resistance and linkage of integrase inhibitor mutations with protease and reverse transcriptase resistance mutations. PLoS One. 7:e40514. doi:10.1371/journal .pone.0040514.
34. White KL, Kulkarni R, Szwarcberg J, Quirk E, Cheng AK, Miller MD. 2012. Integrated analysis of emergent drug resistance from the HIV-1 phase 3 QUAD studies through week 48. Antivir. Ther. 17:A12.
35. Gotte M. 2012. The distinct contributions of fitness and genetic barrier to the development of antiviral drug resistance. Curr. Opin. Virol. 2:644-650.
36. Hare S, Gupta SS, Valkov E, Engelman A, Cherepanov P. 2010. Retroviral intasome assembly and inhibition of DNA strand transfer. Nature 464:232-236.