The mechanism of H171T resistance reveals the importance of Nδ-protonated His171 for the binding of allosteric inhibitor BI-D to HIV-1 integrase

Retrovirology

Volumn 11, Issue 1, 2014, Pages

  Slaughter, Alison ^a   Jurado, Kellie A ^b   Deng, Nanjie ^c   Feng, Lei ^a   Kessl, Jacques J ^a   Shkriabai, Nikoloz ^a   Larue, Ross C ^a   Fadel, Hind J ^d   Patel, Pratiq A ^e   Jena, Nivedita ^e   Fuchs, James R ^e   Poeschla, Eric ^d   Levy, Ronald M ^c   Engelman, Alan ^b   Kvaratskhelia, Mamuka ^a  

^a OHIO STATE UNIVERSITY   (United States)

^b DANA FARBER CANCER INSTITUTE   (United States)

^c Temple University   (United States)

^d Mayo Clinic College of Medicine   (United States)

^e OHIO STATE UNIVERSITY   (United States)

Author keywords

Aberrant multimerization; Allosteric inhibitors; Drug resistance; HIV 1 integrase

Indexed keywords

CARBOXYLIC ACID; INTEGRASE; INTEGRASE INHIBITOR; LENS EPITHELIUM DERIVED GROWTH FACTOR; PROTEIN H171T; PROTEIN P75; UNCLASSIFIED DRUG; ACETIC ACID DERIVATIVE; BI-D COMPOUND; HISTIDINE; MUTANT PROTEIN; P31 INTEGRASE PROTEIN, HUMAN IMMUNODEFICIENCY VIRUS 1; PROTEIN BINDING; QUINOLINE DERIVATIVE;

AMINO ACID SUBSTITUTION; ARTICLE; BINDING AFFINITY; BINDING SITE; CONTROLLED STUDY; DRUG PROTEIN BINDING; ENZYME ACTIVITY; HUMAN; HUMAN CELL; HUMAN IMMUNODEFICIENCY VIRUS 1; HYDROGEN BOND; NONHUMAN; PROTEIN MULTIMERIZATION; PROTON TRANSPORT; VIRUS REPLICATION; VIRUS RESISTANCE; ANTIVIRAL RESISTANCE; CELL LINE; CHEMICAL STRUCTURE; CHEMISTRY; DRUG EFFECTS; ENZYMOLOGY; GENETICS; METABOLISM; MISSENSE MUTATION; PROTEIN CONFORMATION; X RAY CRYSTALLOGRAPHY;

HUMAN IMMUNODEFICIENCY VIRUS 1;

ACETATES; CELL LINE; CRYSTALLOGRAPHY, X-RAY; DRUG RESISTANCE, VIRAL; HISTIDINE; HIV INTEGRASE; HIV INTEGRASE INHIBITORS; HIV-1; HUMANS; MODELS, MOLECULAR; MUTANT PROTEINS; MUTATION, MISSENSE; PROTEIN BINDING; PROTEIN CONFORMATION; QUINOLINES;

EID: 84934915505     PISSN: None     EISSN: 17424690     Source Type: Journal    
DOI: 10.1186/s12977-014-0100-1     Document Type: Article

References (74)

1. Brown PO: Integration. In Retroviruses. Edited by Coffin JM, Hughes SH, Varmus HE. Plainview, NY: Cold Spring Harbor Laboratory; 1997:161-204.
2. Hazuda DJ: HIV integrase as a target for antiretroviral therapy. Curr Opin HIV AIDS 2012, 7:383-389.
3. Sichtig N, Sierra S, Kaiser R, Daumer M, Reuter S, Schulter E, Altmann A, Fatkenheuer G, Dittmer U, Pfister H, Esser S: Evolution of raltegravir resistance during therapy. J Antimicrob Chemother 2009, 64:25-32.
4. 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: Raltegravir with optimized background therapy for resistant HIV-1 infection. N Engl J Med 2008, 359:339-354.
5. Metifiot M, Vandegraaff N, Maddali K, Naumova A, Zhang X, Rhodes D, Marchand C, Pommier Y: Elvitegravir overcomes resistance to raltegravir induced by integrase mutation Y143. AIDS 2011, 25:1175-1178.
6. Wares M, Mesplede T, Quashie PK, Osman N, Han Y, Wainberg MA: 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.
7. Li M, Mizuuchi M, Burke TR Jr, Craigie R: Retroviral DNA integration: reaction pathway and critical intermediates. EMBO J 2006, 25:1295-1304.
8. Hare S, Gupta SS, Valkov E, Engelman A, Cherepanov P: Retroviral intasome assembly and inhibition of DNA strand transfer. Nature 2010, 464:232-236.
9. Maertens GN, Hare S, Cherepanov P: The mechanism of retroviral integration from X-ray structures of its key intermediates. Nature 2010, 468:326-329.
10. Krishnan L, Li X, Naraharisetty HL, Hare S, Cherepanov P, Engelman A: Structure-based modeling of the functional HIV-1 intasome and its inhibition. Proc Natl Acad Sci U S A 2010, 107:15910-15915.
11. Kessl JJ, Li M, Ignatov M, Shkriabai N, Eidahl JO, Feng L, Musier-Forsyth K, Craigie R, Kvaratskhelia M: FRET analysis reveals distinct conformations of IN tetramers in the presence of viral DNA or LEDGF/p75. Nucleic Acids Res 2011, 39:9009-9022.
12. Johnson BC, Metifiot M, Ferris A, Pommier Y, Hughes SH: A homology model of HIV-1 integrase and analysis of mutations designed to test the model. J Mol Biol 2013, 425:2133-2146.
13. McKee CJ, Kessl JJ, Shkriabai N, Dar MJ, Engelman A, Kvaratskhelia M: Dynamic modulation of HIV-1 integrase structure and function by cellular lens epithelium-derived growth factor (LEDGF) protein. J Biol Chem 2008, 283:31802-31812.
14. Kessl JJ, Eidahl JO, Shkriabai N, Zhao Z, McKee CJ, Hess S, Burke TR Jr, Kvaratskhelia M: An allosteric mechanism for inhibiting HIV-1 integrase with a small molecule. Mol Pharmacol 2009, 76:824-832.
15. Cherepanov P, Maertens G, Proost P, Devreese B, Van Beeumen J, Engelborghs Y, De Clercq E, Debyser Z: HIV-1 integrase forms stable tetramers and associates with LEDGF/p75 protein in human cells. J Biol Chem 2003, 278:372-381.
16. Ciuffi A, Llano M, Poeschla E, Hoffmann C, Leipzig J, Shinn P, Ecker JR, Bushman F: A role for LEDGF/p75 in targeting HIV DNA integration. Nat Med 2005, 11:1287-1289.
17. Llano M, Saenz DT, Meehan A, Wongthida P, Peretz M, Walker WH, Teo W, Poeschla EM: An essential role for LEDGF/p75 in HIV integration. Science 2006, 314:461-464.
18. Shun MC, Raghavendra NK, Vandegraaff N, Daigle JE, Hughes S, Kellam P, Cherepanov P, Engelman A: LEDGF/p75 functions downstream from preintegration complex formation to effect gene-specific HIV-1 integration. Genes Dev 2007, 21:1767-1778.
19. Busschots K, Vercammen J, Emiliani S, Benarous R, Engelborghs Y, Christ F, Debyser Z: The interaction of LEDGF/p75 with integrase is lentivirus-specific and promotes DNA binding. J Biol Chem 2005, 280:17841-17847.
20. Cherepanov P, Ambrosio AL, Rahman S, Ellenberger T, Engelman A: Structural basis for the recognition between HIV-1 integrase and transcriptional coactivator p75. Proc Natl Acad Sci U S A 2005, 102:17308-17313.
21. Eidahl JO, Crowe BL, North JA, McKee CJ, Shkriabai N, Feng L, Plumb M, Graham RL, Gorelick RJ, Hess S, Poirier MG, Foster MP, Kvaratskhelia M: Structural basis for high-affinity binding of LEDGF PWWP to mononucleosomes. Nucleic Acids Res 2013, 41:3924-3936.
22. Pradeepa MM, Sutherland HG, Ule J, Grimes GR, Bickmore WA: Psip1/Ledgf p52 binds methylated histone H3K36 and splicing factors and contributes to the regulation of alternative splicing. PLoS Genet 2012, 8:e1002717.
23. van Nuland R, van Schaik FM, Simonis M, van Heesch S, Cuppen E, Boelens R, Timmers HM, van Ingen H: Nucleosomal DNA binding drives the recognition of H3K36-methylated nucleosomes by the PSIP1-PWWP domain. Epigenetics Chromatin 2013, 6:12.
24. Cherepanov P, Sun ZY, Rahman S, Maertens G, Wagner G, Engelman A: Solution structure of the HIV-1 integrase-binding domain in LEDGF/p75. Nat Struct Mol Biol 2005, 12:526-532.
25. Hare S, Di Nunzio F, Labeja A, Wang J, Engelman A, Cherepanov P: Structural basis for functional tetramerization of lentiviral integrase. PLoS Pathog 2009, 5:e1000515.
26. Hare S, Shun MC, Gupta SS, Valkov E, Engelman A, Cherepanov P: A novel co-crystal structure affords the design of gain-of-function lentiviral integrase mutants in the presence of modified PSIP1/LEDGF/p75. PLoS Pathog 2009, 5:e1000259.
27. Fadel HJ, Morrison JH, Saenz DT, Fuchs JR, Kvaratskhelia M, Ekker SC, Poeschla EM: TALEN knockout of the PSIP1 gene in human cells: analyses of HIV-1 replication and allosteric integrase inhibitor mechanism. J Virol 2014, 88:9704-9717.
28. Marshall HM, Ronen K, Berry C, Llano M, Sutherland H, Saenz D, Bickmore W, Poeschla E, Bushman FD: Role of PSIP1/LEDGF/p75 in lentiviral infectivity and integration targeting. PLoS One 2007, 2:e1340.
29. De Rijck J, Vandekerckhove L, Gijsbers R, Hombrouck A, Hendrix J, Vercammen J, Engelborghs Y, Christ F, Debyser Z: Overexpression of the lens epithelium-derived growth factor/p75 integrase binding domain inhibits human immunodeficiency virus replication. J Virol 2006, 80:11498-11509.
30. Jurado KA, Engelman A: Multimodal mechanism of action of allosteric HIV-1 integrase inhibitors. Expert Rev Mol Med 2013, 15:e14.
31. Engelman A, Kessl JJ, Kvaratskhelia M: Allosteric inhibition of HIV-1 integrase activity. Curr Opin Chem Biol 2013, 17:339-345.
32. Demeulemeester J, Chaltin P, Marchand A, De Maeyer M, Debyser Z, Christ F: LEDGINs, non-catalytic site inhibitors of HIV-1 integrase: a patent review (2006-2014). Expert Opin Ther Pat 2014, 24:609-632.
33. Fader LD, Malenfant E, Parisien M, Carson R, Bilodeau F, Landry S, Pesant M, Brochu C, Morin S, Chabot C, Halmos T, Bousquet Y, Bailey MD, Kawai SH, Coulombe R, LaPlante S, Jakalian A, Bhardwaj PK, Wernic D, Schroeder P, Amad M, Edwards P, Garneau M, Duan J, Cordingley M, Bethell R, Mason SW, Bös M, Bonneau P, Poupart MA, et al: Discovery of BI 224436, a Noncatalytic Site Integrase Inhibitor (NCINI) of HIV-1. ACS Med Chem Lett 2014, 5:422-427.
34. Fenwick C, Lamorte L, Bethell R, Bonneau P, Cordingly M, Coulombe R, Duan J, Edwards P, Mason S, Poupart M-A, Simoneau B, Tsantrizos Y, Yoakim C: Discovery of a novel HIV-1 non-catalytic site integrase inhibitor [abstract]. In 4th International Conference on Retroviral Integration. 047th edition. Siena: 2011:s5.
35. Tsantrizos YS, Boes M, Brochu C, Fenwick C, Malenfant E, Mason S, Pesant M: Inhibitors of Human Immunodeficency Virus Repllication. Germany: Boehringer Ingelheim International GmbH; 2007. WO2007/131350.
36. Christ F, Voet A, Marchand A, Nicolet S, Desimmie BA, Marchand D, Bardiot D, Van der Veken NJ, Van Remoortel B, Strelkov SV, De Maeyer M, Chaltin P, Debyser Z: Rational design of small-molecule inhibitors of the LEDGF/p75-integrase interaction and HIV replication. Nat Chem Biol 2010, 6:442-448.
37. Kessl JJ, Jena N, Koh Y, Taskent-Sezgin H, Slaughter A, Feng L, de Silva S, Wu L, Le Grice SF, Engelman A, Fuchs JR, Kvaratskhelia M: A multimode, cooperative mechanism of action of allosteric HIV-1 integrase inhibitors. J Biol Chem 2012, 287:16801-16811.
38. Feng L, Sharma A, Slaughter A, Jena N, Koh Y, Shkriabai N, Larue RC, Patel PA, Mitsuya H, Kessl JJ, Engelman A, Fuchs JR, Kvaratskhelia M: The A128T resistance mutation reveals aberrant protein multimerization as the primary mechanism of action of allosteric HIV-1 integrase inhibitors. J Biol Chem 2013, 288:15813-15820.
39. Jurado KA, Wang H, Slaughter A, Feng L, Kessl JJ, Koh Y, Wang W, Ballandras-Colas A, Patel PA, Fuchs JR, Kvaratskhelia M, Engelman A: Allosteric integrase inhibitor potency is determined through the inhibition of HIV-1 particle maturation. Proc Natl Acad Sci U S A 2013, 110:8690-8695.
40. Tsiang M, Jones GS, Niedziela-Majka A, Kan E, Lansdon EB, Huang W, Hung M, Samuel D, Novikov N, Xu Y, Mitchell M, Guo H, Babaoglu K, Liu X, Geleziunas R, Sakowicz R: New class of HIV-1 integrase (IN) inhibitors with a dual mode of action. J Biol Chem 2012, 287:21189-21203.
41. Gupta K, Brady T, Dyer BM, Malani N, Hwang Y, Male F, Nolte RT, Wang L, Velthuisen E, Jeffrey J, Van Duyne GD, Bushman FD: Allosteric inhibition of human immunodeficiency virus integrase: late block during viral replication and abnormal multimerization involving specific protein domains. J Biol Chem 2014, 289:20477-20488.
42. Le Rouzic E, Bonnard D, Chasset S, Bruneau JM, Chevreuil F, Le Strat F, Nguyen J, Beauvoir R, Amadori C, Brias J, Vomscheid S, Eiler S, Lévy N, Delelis O, Deprez E, Saïb A, Zamborlini A, Emiliani S, Ruff M, Ledoussal B, Moreau F, Benarous R: Dual inhibition of HIV-1 replication by integrase-LEDGF allosteric inhibitors is predominant at the post-integration stage. Retrovirology 2013, 10:144.
43. Christ F, Shaw S, Demeulemeester J, Desimmie BA, Marchand A, Butler S, Smets W, Chaltin P, Westby M, Debyser Z, Pickford C: Small-molecule inhibitors of the LEDGF/p75 binding site of integrase block HIV replication and modulate integrase multimerization. Antimicrob Agents Chemother 2012, 56:4365-4374.
44. Sharma A, Slaughter A, Jena N, Feng L, Kessl JJ, Fadel HJ, Malani N, Male F, Wu L, Poeschla E, Bushman FD, Fuchs JR, Kvaratskhelia M: A new class of multimerization selective inhibitors of HIV-1 Integrase. PLoS Pathog 2014, 10:e1004171.
45. Balakrishnan M, Yant SR, Tsai L, O'Sullivan C, Bam RA, Tsai A, Niedziela-Majka A, Stray KM, Sakowicz R, Cihlar T: Non-catalytic site HIV-1 integrase inhibitors disrupt core maturation and induce a reverse transcription block in target cells. PLoS One 2013, 8:e74163.
46. Desimmie BA, Schrijvers R, Demeulemeester J, Borrenberghs D, Weydert C, Thys W, Vets S, Van Remoortel B, Hofkens J, De Rijck J, Hendrix J, Bannert N, Gijsbers R, Christ F, Debyser Z: LEDGINs inhibit late stage HIV-1 replication by modulating integrase multimerization in the virions. Retrovirology 2013, 10:57.
47. Engelman A, Englund G, Orenstein JM, Martin MA, Craigie R: Multiple effects of mutations in human immunodeficiency virus type 1 integrase on viral replication. J Virol 1995, 69:2729-2736.
48. Engelman A: In vivo analysis of retroviral integrase structure and function. Adv Virus Res 1999, 52:411-426.
49. Engelman A: Pleiotropic nature of HIV-1 integrase mutations. In HIV-1 Integrase: Mechanism and Inhibitor Design. Edited by Neamati N. Hoboken: John Wiley & Sons; 2011:67-81.
50. Bukovsky A, Gottlinger H: Lack of integrase can markedly affect human immunodeficiency virus type 1 particle production in the presence of an active viral protease. J Virol 1996, 70:6820-6825.
51. Cannon PM, Wilson W, Byles E, Kingsman SM, Kingsman AJ: Human immunodeficiency virus type 1 integrase: effect on viral replication of mutations at highly conserved residues. J Virol 1994, 68:4768-4775.
52. Fenwick CW, Tremblay S, Wardrop E, Bethell R, Coulomb R, Elston R, Faucher AM, Mason S, Simoneau B, Tsantrizos Y, Yoakim C: Resistance studies with HIV-1 non-catalytic site integrase inhibitors [abstract]. Antivir Ther 2011, 16(Suppl 1):A9.
53. Wang H, Jurado KA, Wu X, Shun MC, Li X, Ferris AL, Smith SJ, Patel PA, Fuchs JR, Cherepanov P, Kvaratskhelia M, Hughes SH, Engelman A: HRP2 determines the efficiency and specificity of HIV-1 integration in LEDGF/p75 knockout cells but does not contribute to the antiviral activity of a potent LEDGF/p75-binding site integrase inhibitor. Nucleic Acids Res 2012, 40:11518-11530.
54. Kotova S, Li M, Dimitriadis EK, Craigie R: Nucleoprotein intermediates in HIV-1 DNA integration visualized by atomic force microscopy. J Mol Biol 2010, 399:491-500.
55. Rhee SY, Liu TF, Kiuchi M, Zioni R, Gifford RJ, Holmes SP, Shafer RW: Natural variation of HIV-1 group M integrase: implications for a new class of antiretroviral inhibitors. Retrovirology 2008, 5:74.
56. Fader LD, Carson R, Morin S, Bilodeau F, Chabot C, Halmos T, Bailey MD, Kawai SH, Coulombe R, Laplante S, Mekhssian K, Jakalian A, Garneau M, Duan J, Mason SW, Simoneau B, Fenwick C, Tsantrizos Y, Yoakim C: Minimizing the contribution of enterohepatic recirculation to clearance in rat for the NCINI class of inhibitors of HIV. ACS Med Chem Lett 2014, 5:711-716.
57. Brown HE, Chen H, Engelman A: Structure-based mutagenesis of the human immunodeficiency virus type 1 DNA attachment site: effects on integration and cDNA synthesis. J Virol 1999, 73:9011-9020.
58. Lu R, Limon A, Devroe E, Silver PA, Cherepanov P, Engelman A: Class II integrase mutants with changes in putative nuclear localization signals are primarily blocked at a postnuclear entry step of human immunodeficiency virus type 1 replication. J Virol 2004, 78:12735-12746.
59. Connor RI, Chen BK, Choe S, Landau NR: Vpr is required for efficient replication of human immunodeficiency virus type-1 in mononuclear phagocytes. Virology 1995, 206:935-944.
60. Fadel HJ, Morrison J, Saenz D, Ekker SC, Fuchs JR, Kvaratskhelia M, Poeschla EM: Conference on Retroviruses and Opportunistic Infections; March 3-6. Boston: IAS-USA/CROI Foundation; 2014:177.
61. Otwinowski Z, Minor W: Processing of X-ray diffraction data collected in oscillation mode. In Methods in Enzymology, Volume 276. Edited by Carter CW, Sweet RM. New York: Academic; 1997:307-326.
62. McCoy AJ, Grosse-Kunstleve RW, Adams PD, Winn MD, Storoni LC, Read RJ: Phaser crystallographic software. J Appl Crystallogr 2007, 40:658-674.
63. Emsley P, Lohkamp B, Scott WG, Cowtan K: Features and development of Coot. Acta Crystallogr D Biol Crystallogr 2010, 66:486-501.
64. Murshudov GN, Vagin AA, Dodson EJ: Refinement of macromolecular structures by the maximum-likelihood method. Acta Crystallogr D Biol Crystallogr 1997, 53:240-255.
65. Gilson MK, Given JA, Bush BL, McCammon JA: The statistical-thermodynamic basis for computation of binding affinities: a critical review. Biophys J 1997, 72:1047-1069.
66. Boresch S, Tettinger F, Leitgeb M, Karplus M: Absolute binding free energies: a quantitative approach for their calculation. J Phys Chem B 2003, 107:9535-9551.
67. Wang J, Deng Y, Roux B: Absolute binding free energy calculations using molecular dynamics simulations with restraining potentials. Biophys J 2006, 91:2798-2814.
68. Deng NJ, Zhang P, Cieplak P, Lai L: Elucidating the energetics of entropically driven protein-ligand association: calculations of absolute binding free energy and entropy. J Phys Chem B 2011, 115:11902-11910.
69. Jorgensen WL, Chandrasekhar J, Madura JD, Impey RW, Klein ML: Comparison of simple potential functions for simulating liquid water. J Chem Phys 1983, 79:926-935.
70. Lindorff-Larsen K, Piana S, Palmo K, Maragakis P, Klepeis JL, Dror RO, Shaw DE: Improved side-chain torsion potentials for the Amber ff99SB protein force field. Proteins 2010, 78:1950-1958.
71. Wang J, Wolf RM, Caldwell JW, Kollman PA, Case DA: Development and testing of a general amber force field. J Comput Chem 2004, 25:1157-1174.
72. Jakalian A, Jack DB, Bayly CI: Fast, efficient generation of high-quality atomic charges. AM1-BCC model: II. Parameterization and validation. J Comput Chem 2002, 23:1623-1641.
73. Hess B, Kutzner C, Van Der Spoel D, Lindahl E: GROMACS 4: algorithms for highly efficient, load-balanced, and scalable molecular simulation. J Chem Theor Comput 2008, 4:435-447.
74. Pronk S, Pall S, Schulz R, Larsson P, Bjelkmar P, Apostolov R, Shirts MR, Smith JC, Kasson PM, van der Spoel D, Hess B, Lindahl E: GROMACS 4.5: a high-throughput and highly parallel open source molecular simulation toolkit. Bioinformatics (Oxford, England) 2013, 29:845-854.