Different pathways leading to integrase inhibitors resistance

Frontiers in Microbiology

Volumn 7, Issue JAN, 2017, Pages

  Thierry, Eloïse ^a   Deprez, Eric ^a   Delelis, Olivier ^a  

^a UNIVERSITÉ PARIS SACLAY   (France)

Author keywords

HIV 1; Integrase; Strand transfer inhibitors; Unintegrated viral DNA; Viral resistance

Indexed keywords

BI 224436; DOLUTEGRAVIR; ELVITEGRAVIR; INTEGRASE INHIBITOR; OLIGONUCLEOTIDE; RALTEGRAVIR; UNCLASSIFIED DRUG; VIRAL PROTEIN; VIRUS DNA;

ANTIVIRAL RESISTANCE; CATALYSIS; DRUG TARGETING; ENZYME ACTIVITY; GENE EXPRESSION; GENE MUTATION; HUMAN; HUMAN IMMUNODEFICIENCY VIRUS 1; HUMAN IMMUNODEFICIENCY VIRUS INFECTION; LONG TERMINAL REPEAT; NONHUMAN; PHASE 1 CLINICAL TRIAL (TOPIC); PROTOTYPE FOAMY VIRUS 1; REVIEW; SPUMAVIRUS; VIRUS DNA CELL DNA INTERACTION; VIRUS REPLICATION;

EID: 85011968885     PISSN: None     EISSN: 1664302X     Source Type: Journal    
DOI: 10.3389/fmicb.2016.02165     Document Type: Review

References (172)

1. Akil, B., Blick, G., Hagins, D. P., Ramgopal, M. N., Richmond, G. J., Samuel, R. M., et al. (2015). Dolutegravir versus placebo in subjects harbouring HIV-1 with integrase inhibitor resistance associated substitutions: 48-week results from VIKING-4, a randomized study. Antivir. Ther. 20, 343-348. doi: 10.3851/IMP2878
2. Al-Mawsawi, L. Q., Christ, F., Dayam, R., Debyser, Z., and Neamati, N. (2008). Inhibitory profile of a LEDGF/p75 peptide against HIV-1 integrase: insight into integrase-DNA complex formation and catalysis. FEBS Lett. 582, 1425-1430. doi: 10.1016/J.Febslet.2008.02.076
3. Anstett, K., Mesplede, T., Oliveira, M., Cutillas, V., and Wainberg, M. A. (2015). Dolutegravir resistance mutation R263K cannot coexist in combination with many classical integrase inhibitor resistance substitutions. J. Virol. 89, 4681-4684. doi: 10.1128/JVI.03485-14
4. Asante-Appiah, E., and Skalka, A. M. (1999). HIV-1 integrase: structural organization, conformational changes, and catalysis. Adv. Virus Res. 52, 351-369.
5. Balakrishnan, M., Yant, S. R., Tsai, L., O'Sullivan, C., Bam, R. A., Tsai, A., et al. (2013). Non-catalytic site HIV-1 integrase inhibitors disrupt core maturation and induce a reverse transcription block in target cells. PLoS ONE 8:e74163. doi: 10.1371/journal.pone.0074163
6. Baranova, S., Tuzikov, F. V., Zakharova, O. D., Tuzikova, N. A., Calmels, C., Litvak, S., et al. (2007). Small-angle X-ray characterization of the nucleoprotein complexes resulting from DNA-induced oligomerization of HIV-1 integrase. Nucleic Acids Res. 35, 975-987. doi: 10.1093/Nar/Gkl1111
7. Baroncelli, S., Pirillo, M. F., Galluzzo, C. M., Antoni, A. D., Ladisa, N., Francisci, D., et al. (2015). Rate and determinants of residual viremia in multidrug-experienced patients successfully treated with raltegravir-based regimens. AIDS Res. Hum. Retroviruses 31, 71-77. doi: 10.1089/AID.2014.0060
8. Benleulmi, M. S., Matysiak, J., Henriquez, D. R., Vaillant, C., Lesbats, P., Calmels, C., et al. (2015). Intasome architecture and chromatin density modulate retroviral integration into nucleosome. Retrovirology 12:13. doi: 10.1186/s12977-015-0145-9
9. Botbol, Y. R., Raghavendra, N. K., Rahman, S., Engelman, A., and Lavigne, M. (2008). Chromatinized templates reveal the requirement for the LEDGF/p75 PWWP domain during HIV-1 integration in vitro. Nucleic Acids Res. 36, 1237-1246. doi: 10.1093/Nar/Gkm1127
10. Brown, H. E. V., Chen, H. M., and Engelman, A. (1999). Structure-based mutagenesis of the human immunodeficiency virus type 1 DNA attachment site: effects on integration and cDNA synthesis. J. Virol. 73, 9011-9020.
11. Brussel, A., and Sonigo, P. (2004). Evidence for gene expression by unintegrated human immunodeficiency virus type 1 DNA species. J. Virol. 78, 11263-11271.
12. Butler, S. L., Johnson, E. P., and Bushman, F. D. (2002). Human immunodeficiency virus cDNA metabolism: notable stability of two-long terminal repeat circles. J. Virol. 76, 3739-3747.
13. Buzon, M. J., Dalmau, J., Puertas, M. C., Puig, J., Clotet, B., and Martinez-Picado, J. (2010a). The HIV-1 integrase genotype strongly predicts raltegravir susceptibility but not viral fitness of primary virus isolates. AIDS 24, 17-25. doi: 10.1097/Qad.0b013e328331c81e
14. Buzon, M. J., Massanella, M., Llibre, J. M., Esteve, A., Dahl, V., Puertas, M. C., et al. (2010b). HIV-1 replication and immune dynamics are affected by raltegravir intensification of HAART-suppressed subjects. Nat. Med. 16, 460-465. doi: 10.1038/Nm.2111
15. Campbell, E. M., and Hope, T. J. (2015). HIV-1 capsid: the multifaceted key player in HIV-1 infection. Nat. Rev. Microbiol. 13, 471-483. doi: 10.1038/nrmicro3503
16. Canducci, F., Ceresola, E. R., Saita, D., Castagna, A., Gianotti, N., Underwood, M., et al. (2013). In vitro phenotypes to elvitegravir and dolutegravir in primary macrophages and lymphocytes of clonal recombinant viral variants selected in patients failing raltegravir. J. Antimicrob. Chemother. 68, 2525-2532. doi: 10.1093/jac/dkt220
17. Cara, A., Cereseto, A., Lori, F., and Reitz, M. S. Jr. (1996). HIV-1 protein expression from synthetic circles of DNA mimicking the extrachromosomal forms of viral DNA. J. Biol. Chem. 271, 5393-5397.
18. Carayon, K., Leh, H., Henry, E., Simon, F., Mouscadet, J. F., and Deprez, E. (2010). A cooperative and specific DNA-binding mode of HIV-1 integrase depends on the nature of the metallic cofactor and involves the zinc-containing N-terminal domain. Nucleic Acids Res. 38, 3692-3708. doi: 10.1093/nar/gkq087
19. Castagna, A., Maggiolo, F., Penco, G., Wright, D., Mills, A., Grossberg, R., et al. (2014). Dolutegravir in antiretroviral-experienced patients with raltegravir-and/or elvitegravir-resistant HIV-1: 24-week results of the phase III VIKING-3 study. J. Infect. Dis. 210, 354-362. doi: 10.1093/infdis/jiu051
20. Chan, C. N., Trinite, B., Lee, C. S., Mahajan, S., Anand, A., Wodarz, D., et al. (2016). HIV-1 latency and virus production from unintegrated genomes following direct infection of resting CD4 T cells. Retrovirology 13:1. doi: 10.1186/s12977-015-0234-9
21. Charpentier, C., Roquebert, B., Delelis, O., Larrouy, L., Matheron, S., Tubiana, R., et al. (2011). Hot spots of integrase genotypic changes leading to HIV-2 resistance to raltegravir. Antimicrob. Agents Chemother. 55, 1293-1295. doi: 10.1128/AAC.00942-10
22. Chen, J. C. H., Krucinski, J., Miercke, L. J. W., Finer-Moore, J. S., Tang, A. H., Leavitt, A. D., et al. (2000). Crystal structure of the HIV-1 integrase catalytic core and C-terminal domains: a model for viral DNA binding. Proc. Natl. Acad. Sci. U.S.A. 97, 8233-8238.
23. Cherepanov, P., Ambrosio, A. L., Rahman, S., Ellenberger, T., and Engelman, A. (2005a). Structural basis for the recognition between HIV-1 integrase and transcriptional coactivator p75. Proc. Natl. Acad. Sci. U.S.A. 102, 17308-17313. doi: 10.1073/pnas.0506924102
24. Cherepanov, P., Maertens, G., Proost, P., Devreese, B., Van Beeumen, J., Engelborghs, Y., et al. (2003). HIV-1 integrase forms stable tetramers and associates with LEDGF/p75 protein in human cells. J. Biol. Chem. 278, 372-381. doi: 10.1074/Jbc.M209278200
25. Cherepanov, P., Sun, Z. Y., Rahman, S., Maertens, G., Wagner, G., and Engelman, A. (2005b). Solution structure of the HIV-1 integrase-binding domain in LEDGF/p75. Nat. Struct. Mol. Biol. 12, 526-532. doi: 10.1038/nsmb937
26. Christ, F., and Debyser, Z. (2013). The LEDGF/p75 integrase interaction, a novel target for anti-HIV therapy. Virology 435, 102-109. doi: 10.1016/j.virol.2012.09.033
27. Christ, F., Shaw, S., Demeulemeester, J., Desimmie, B. A., Marchand, A., Butler, S., et al. (2012). Small-molecule inhibitors of the LEDGF/p75 binding site of integrase block HIV replication and modulate integrase multimerization. Antimicrob. Agents Chemother. 56, 4365-4374. doi: 10.1128/AAC.00717-12
28. Christ, F., Voet, A., Marchand, A., Nicolet, S., Desimmie, B. A., Marchand, D., et al. (2010). Rational design of small-molecule inhibitors of the LEDGF/p75-integrase interaction and HIV replication. Nat. Chem. Biol. 6, 442-448. doi: 10.1038/nchembio.370
29. Chun, T. W., Carruth, L., Finzi, D., Shen, X., DiGiuseppe, J. A., Taylor, H., et al. (1997). Quantification of latent tissue reservoirs and total body viral load in HIV-1 infection. Nature 387, 183-188. doi: 10.1038/387183a0
30. Cooper, D. A., Steigbigel, R. T., Gatell, J. M., Rockstroh, J. K., Katlama, C., Yeni, P., et al. (2008). Subgroup and resistance analyses of raltegravir for resistant HIV-1 infection. N. Engl. J. Med. 359, 355-365.
31. Cutillas, V., Mesplede, T., Anstett, K., Hassounah, S., and Wainberg, M. A. (2015). The R262K substitution combined with H51Y in HIV-1 subtype B integrase confers low-level resistance against dolutegravir. Antimicrob. Agents Chemother. 59, 310-316. doi: 10.1128/AAC.04274-14
32. da Silva, D., Van Wesenbeeck, L., Breilh, D., Reigadas, S., Anies, G., Van Baelen, K., et al. (2010). HIV-1 resistance patterns to integrase inhibitors in antiretroviral-experienced patients with virological failure on raltegravir-containing regimens. J. Antimicrob. Chemother. 65, 1262-1269. doi: 10.1093/Jac/Dkq099
33. De Luca, L., Barreca, M. L., Ferro, S., Christ, F., Iraci, N., Gitto, R., et al. (2009). Pharmacophore-based discovery of small-molecule inhibitors of protein-protein interactions between HIV-1 integrase and cellular cofactor LEDGF/p75. ChemMedChem 4, 1311-1316. doi: 10.1002/Cmdc.200900070
34. De Luca, L., Ferro, S., Gitto, R., Barreca, M. L., Agnello, S., Christ, F., et al. (2010). Small molecules targeting the interaction between HIV-1 integrase and LEDGF/p75 cofactor. Bioorg. Med. Chem. 18, 7515-7521. doi: 10.1016/j.bmc.2010.08.051
35. De Rijck, J., Vandekerckhove, L., Gijsbers, R., Hombrouck, A., Hendrix, J., Vercammen, J., et al. (2006). Overexpression of the lens epithelium-derived growth factor/p75 integrase binding domain inhibits human immunodeficiency virus replication. J. Virol. 80, 11498-11509. doi: 10.1128/Jvi.00801-06
36. DeAnda, F., Hightower, K. E., Nolte, R. T., Hattori, K., Yoshinaga, T., Kawasuji, T., et al. (2013). Dolutegravir interactions with HIV-1 integrase-DNA: structural rationale for drug resistance and dissociation kinetics. PLoS ONE 8:e77448. doi: 10.1371/journal.pone.0077448
37. Debyser, Z., Christ, F., De Rijck, J., and Gijsbers, R. (2015). Host factors for retroviral integration site selection. Trends Biochem. Sci. 40, 108-116. doi: 10.1016/j.tibs.2014.12.001
38. Delelis, O., Carayon, K., Guiot, E., Leh, H., Tauc, P., Brochon, J. C., et al. (2008a). Insight into the integrase-DNA recognition mechanism-A specific DNA-binding mode revealed by an enzymatically labeled integrase. J. Biol. Chem. 283, 27838-27849. doi: 10.1074/Jbc.M803257200
39. Delelis, O., Carayon, K., Saib, A., Deprez, E., and Mouscadet, J. F. (2008b). Integrase and integration: biochemical activities of HIV-1 integrase. Retrovirology 5:114. doi: 10.1186/1742-4690-5-114
40. Delelis, O., Lehmann-Che, J., and Saib, A. (2004). Foamy viruses-a world apart. Curr. Opin. Microbiol. 7, 400-406. doi: 10.1016/j.mib.2004.06.009
41. Delelis, O., Malet, I., Na, L., Tchertanov, L., Calvez, V., Marcelin, A. G., et al. (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. doi: 10.1093/nar/gkn1050
42. Delelis, O., Parissi, V., Leh, H., Mbemba, G., Petit, C., Sonigo, P., et al. (2007). Efficient and specific internal cleavage of a retroviral palindromic DNA sequence by tetrameric HIV-1 integrase. PLoS ONE 2:e608. doi: 10.1371/journal.pone.0000608
43. Delelis, O., Petit, C., Leh, H., Mbemba, G., Mouscadet, J. F., and Sonigo, P. (2005). A novel function for spumaretrovirus integrase: an early requirement for integrase-mediated cleavage of 2 LTR circles. Retrovirology 2:31. doi: 10.1186/1742-4690-2-31
44. Delelis, O., Thierry, S., Subra, F., Simon, F., Malet, I., Alloui, C., et al. (2010). Impact of Y143 HIV-1 integrase mutations on resistance to Raltegravir in vitro and in vivo. Antimicrob. Agents Chemother. 54, 491-501. doi: 10.1128/AAC.01075-09
45. Demeulemeester, J., Chaltin, P., Marchand, A., De Maeyer, M., Debyser, Z., and Christ, F. (2014). LEDGINs, non-catalytic site inhibitors of HIV-1 integrase: a patent review (2006-2014). Expert Opin. Ther. Pat. 24, 609-632. doi: 10.1517/13543776.2014.898753
46. Deprez, E., Barbe, S., Kolaski, M., Leh, H., Zouhiri, F., Auclair, C., et al. (2004). Mechanism of HIV-1 integrase inhibition by styrylquinoline derivatives in vitro. Mol. Pharmacol. 65, 85-98.
47. Deprez, E., Tauc, P., Leh, H., Mouscadet, J. F., Auclair, C., and Brochon, J. C. (2000). Oligomeric states of the HIV-1 integrase as measured by time-resolved fluorescence anisotropy. Biochemistry 39, 9275-9284. doi: 10.1021/Bi000397j
48. Deprez, E., Tauc, P., Leh, H., Mouscadet, J. F., Auclair, C., Hawkins, M. E., et al. (2001). DNA binding induces dissociation of the multimeric form of HIV-1 integrase: a time-resolved fluorescence anisotropy study. Proc. Natl. Acad. Sci. U.S.A. 98, 10090-10095.
49. Desimmie, B. A., Humbert, M., Lescrinier, E., Hendrix, J., Vets, S., Gijsbers, R., et al. (2012). Phage display-directed discovery of LEDGF/p75 binding cyclic peptide inhibitors of HIV replication. Mol. Ther. 20, 2064-2075. doi: 10.1038/mt.2012.132
50. Desimmie, B. A., Schrijvers, R., Demeulemeester, J., Borrenberghs, D., Weydert, C., Thys, W., et al. (2013). LEDGINs inhibit late stage HIV-1 replication by modulating integrase multimerization in the virions. Retrovirology 10:57. doi: 10.1186/1742-4690-10-57
51. Dinoso, J. B., Kim, S. Y., Wiegand, A. M., Palmer, S. E., Gange, S. J., Cranmer, L., et al. (2009). Treatment intensification does not reduce residual HIV-1 viremia in patients on highly active antiretroviral therapy. Proc. Natl. Acad. Sci. U.S.A. 106, 9403-9408. doi: 10.1073/pnas.0903107106
52. Du, L., Zhao, Y. X., Yang, L. M., Zheng, Y. T., Tang, Y., Shen, X., et al. (2008). Symmetrical 1-pyrrolidineacetamide showing anti-HIV activity through a new binding site on HIV-1 integrase. Acta Pharmacol. Sin. 29, 1261-1267. doi: 10.1111/J.1745-7254.2008.00863.X
53. Egbertson, M. S. (2007). HIV integrase inhibitors: from diketoacids to Heterocyclic templates: a history of HIV integrase medicinal chemistry at Merck west point and Merck Rome (IRBM). Curr. Top. Med. Chem. 7, 1251-1272.
54. Emiliani, S., Mousnier, A., Busschots, K., Maroun, M., Van Maele, B., Tempe, D., et al. (2005). Integrase mutants defective for interaction with LEDGF/p75 are impaired in chromosome tethering and HIV-1 replication. J. Biol. Chem. 280, 25517-25523.
55. Engelman, A., Bushman, F. D., and Craigie, R. (1993). Identification of discrete functional domains of Hiv-1 integrase and their organization within an active multimeric complex. EMBO J. 12, 3269-3275.
56. Engelman, A., and Cherepanov, P. (2008). The lentiviral integrase binding protein LEDGF/p75 and HIV-1 replication. PLoS Pathog. 4:E1000046. doi: 10.1371/Journal.Ppat.1000046
57. Engelman, A., and Cherepanov, P. (2012). The structural biology of HIV-1: mechanistic and therapeutic insights. Nat. Rev. Microbiol. 10, 279-290. doi: 10.1038/nrmicro2747
58. Eron, J. J., Clotet, B., Durant, J., Katlama, C., Kumar, P., Lazzarin, A., et al. (2013). 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. 207, 740-748. doi: 10.1093/infdis/jis750
59. Espeseth, A. S., Felock, P., Wolfe, A., Witmer, M., Grobler, J., Anthony, N., et al. (2000). HIV-1 integrase inhibitors that compete with the target DNA substrate define a unique strand transfer conformation for integrase. Proc. Natl. Acad. Sci. U.S.A. 97, 11244-11249.
60. Esposito, D., and Craigie, R. (1998). Sequence specificity of viral end DNA binding by HIV-1 integrase reveals critical regions for protein-DNA interaction. EMBO J. 17, 5832-5843.
61. Fadel, H. J., Morrison, J. H., Saenz, D. T., Fuchs, J. R., Kvaratskhelia, M., Ekker, S. C., et al. (2014). TALEN knockout of the PSIP1 gene in human cells: analyses of HIV-1 replication and allosteric integrase inhibitor mechanism. J. Virol. 88, 9704-9717. doi: 10.1128/JVI.01397-14
62. Fader, L. D., Malenfant, E., Parisien, M., Carson, R., Bilodeau, F., Landry, S., et al. (2014). Discovery of BI 224436, a noncatalytic site integrase inhibitor (NCINI) of HIV-1. ACS Med. Chem. Lett. 5, 422-427. doi: 10.1021/ml500002n
63. Fan, X., Zhang, F. H., Al-Safi, R. I., Zeng, L. F., Shabaik, Y., Debnath, B., et al. (2011). Design of HIV-1 integrase inhibitors targeting the catalytic domain as well as its interaction with LEDGF/p75: a scaffold hopping approach using salicylate and catechol groups. Bioorg. Med. Chem. 19, 4935-4952. doi: 10.1016/j.bmc.2011.06.058
64. Faure, A., Calmels, C., Desjobert, C., Castroviejo, M., Caumont-Sarcos, A., Tarrago-Litvak, L., et al. (2005). HIV-1 integrase crosslinked oligomers are active in vitro. Nucleic Acids Res. 33, 977-986. doi: 10.1093/Nar/Gki241
65. Fenwick, C., Amad, M., Bailey, M. D., Bethell, R., Bos, M., Bonneau, P., et al. (2014). Preclinical profile of BI 224436, a novel HIV-1 non-catalytic-site integrase inhibitor. Antimicrob. Agents Chemother. 58, 3233-3244. doi: 10.1128/AAC.02719-13
66. Fransen, S., Gupta, S., Danovich, R., Hazuda, D., Miller, M., Witmer, M., et al. (2009). Loss of raltegravir susceptibility by human immunodeficiency virus type 1 is conferred via multiple nonoverlapping genetic pathways. J. Virol. 83, 11440-11446. doi: 10.1128/Jvi.01168-09
67. Gandhi, R. T., Zheng, L., Bosch, R. J., Chan, E. S., Margolis, D. M., Read, S., et al. (2010). The effect of raltegravir intensification on low-level residual viremia in HIV-infected patients on antiretroviral therapy: a randomized controlled trial. PLoS Med. 7:321. doi: 10.1371/journal.pmed.1000321
68. Gelderblom, H. C., Vatakis, D. N., Burke, S. A., Lawrie, S. D., Bristol, G. C., and Levy, D. N. (2008). Viral complementation allows HIV-1 replication without integration. Retrovirology 5:60. doi: 10.1186/1742-4690-5-60
69. Gerard, A., Segeral, E., Naughtin, M., Abdouni, A., Charmeteau, B., Cheynier, R., et al. (2015). The integrase cofactor LEDGF/p75 associates with Iws1 and Spt6 for postintegration silencing of HIV-1 gene expression in latently infected cells. Cell Host Microbe 17, 107-117. doi: 10.1016/j.chom.2014.12.002
70. Gerton, J. L., and Brown, P. O. (1997). The core domain of HIV-1 integrase recognizes key features of its DNA substrates. J. Biol. Chem. 272, 25809-25815.
71. Gillim-Ross, L., Cara, A., and Klotman, M. E. (2005). HIV-1 extrachromosomal 2-LTR circular DNA is long-lived in human macrophages. Viral Immunol. 18, 190-196.
72. Goldgur, Y., Dyda, F., Hickman, A. B., Jenkins, T. M., Craigie, R., and Davies, D. R. (1998). Three new structures of the core domain of HIV-1 integrase: an active site that binds magnesium. Proc. Natl. Acad. Sci. U.S.A. 95, 9150-9154.
73. Grinsztejn, B., Nguyen, B. Y., Katlama, C., Gatell, J. M., Lazzarin, A., Vittecoq, D., et al. (2007). Safety and efficacy of the HIV-1 integrase inhibitor raltegravir (MK-0518) in treatment-experienced patients with multidrug-resistant virus: a phase II randomised controlled trial. Lancet 369, 1261-1269.
74. Guiot, E., Carayon, K., Delelis, O., Simon, F., Tauc, P., Zubin, E., et al. (2006). Relationship between the oligomeric status of HIV-1 integrase on DNA and enzymatic activity. J. Biol. Chem. 281, 22707-22719. doi: 10.1074/jbc.M602198200
75. Gunthard, H. F., Frost, S. D., Leigh-Brown, A. J., Ignacio, C. C., Kee, K., Perelson, A. S., et al. (1999). Evolution of envelope sequences of human immunodeficiency virus type 1 in cellular reservoirs in the setting of potent antiviral therapy. J. Virol. 73, 9404-9412.
76. Hachiya, A., Ode, H., Matsuda, M., Kito, Y., Shigemi, U., Matsuoka, K., et al. (2015). Natural polymorphism S119R of HIV-1 integrase enhances primary INSTI resistance. Antiviral Res. 119, 84-88. doi: 10.1016/j.antiviral.2015.04.014
77. Hamamoto, S., Nishitsuji, H., Amagasa, T., Kannagi, M., and Masuda, T. (2006). Identification of a novel human immunodeficiency virus type 1 integrase interactor, Gemin2, that facilitates efficient viral cDNA synthesis in vivo. J. Virol. 80, 5670-5677. doi: 10.1128/Jvi.02471-05
78. Hare, S., Gupta, S. S., Valkov, E., Engelman, A., and Cherepanov, P. (2010a). Retroviral intasome assembly and inhibition of DNA strand transfer. Nature 464, 232-236. doi: 10.1038/Nature08784
79. Hare, S., Maertens, G. N., and Cherepanov, P. (2012). 3'-processing and strand transfer catalysed by retroviral integrase in crystallo. EMBO J. 31, 3020-3028. doi: 10.1038/emboj.2012.118
80. Hare, S., Smith, S. J., Metifiot, M., Jaxa-Chamiec, A., Pommier, Y., Hughes, S. H., et al. (2011). Structural and functional analyses of the second-generation integrase strand transfer inhibitor dolutegravir (S/GSK1349572). Mol. Pharmacol. 80, 565-572. doi: 10.1124/mol.111.073189
81. Hare, S., Vos, A. M., Clayton, R. F., Thuring, J. W., Cummings, M. D., and Cherepanov, P. (2010b). Molecular mechanisms of retroviral integrase inhibition and the evolution of viral resistance. Proc. Natl. Acad. Sci. U.S.A. 107, 20057-20062. doi: 10.1073/pnas.1010246107
82. Hatano, H., Hayes, T. L., Dahl, V., Sinclair, E., Lee, T. H., Hoh, R., et al. (2011). A randomized, controlled trial of raltegravir intensification in antiretroviral-treated. HIV-infected patients with a suboptimal CD4+ T cell response. J. Infect. Dis. 203, 960-968. doi: 10.1093/infdis/jiq138
83. Hayouka, Z., Hurevich, M., Levin, A., Benyamini, H., Iosub, A., Maes, M., et al. (2010a). Cyclic peptide inhibitors of HIV-1 integrase derived from the LEDGF/p75 protein. Bioorg. Med. Chem. 18, 8388-8395. doi: 10.1016/j.bmc.2010.09.046
84. Hayouka, Z., Levin, A., Maes, M., Hadas, E., Shalev, D. E., Volsky, D. J., et al. (2010b). Mechanism of action of the HIV-1 integrase inhibitory peptide LEDGF 361-370. Biochem. Biophys. Res. Commun. 394, 260-265. doi: 10.1016/J.Bbrc.2010.02.100
85. Hayouka, Z., Rosenbluh, J., Levin, A., Kotler, M., Loyter, A., and Friedler, A. (2007). Inhibiting proteins by shifting their oligomerization equilibrium: application for HIV-1 integrase. Biopolymers 88, 519-519.
86. Hightower, K. E., Wang, R., Deanda, F., Johns, B. A., Weaver, K., Shen, Y., et al. (2011). Dolutegravir (S/GSK1349572) exhibits significantly slower dissociation than raltegravir and elvitegravir from wild-type and integrase inhibitor-resistant HIV-1 integrase-DNA complexes. Antimicrob. Agents Chemother. 55, 4552-4559. doi: 10.1128/AAC.00157-11
87. Hou, Y., McGuinness, D. E., Prongay, A. J., Feld, B., Ingravallo, P., Ogert, R. A., et al. (2008). Screening for antiviral inhibitors of the HIV integrase-LEDGF/p75 interaction using the AlphaScreen (TM) luminescent proximity assay. J. Biomol. Screen. 13, 406-414. doi: 10.1177/1087057108317060
88. Hu, W. S., and Hughes, S. H. (2012). HIV-1 reverse transcription. Cold Spring Harb. Perspect. Med. 2:a006882. doi: 10.1101/cshperspect.a006882
89. Huang, W., Frantzell, A., Fransen, S., and Petropoulos, C. J. (2013). 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. Antimicrob. Agents Chemother. 57, 4105-4113. doi: 10.1128/AAC.00204-13
90. Iyer, S. R., Yu, D., Biancotto, A., Margolis, L. B., and Wu, Y. (2009). Measurement of human immunodeficiency virus type 1 preintegration transcription by using Rev-dependent Rev-CEM cells reveals a sizable transcribing DNA population comparable to that from proviral templates. J. Virol. 83, 8662-8673. doi: 10.1128/JVI.00874-09
91. Juretzek, T., Holm, T., Gartner, K., Kanzler, S., Lindemann, D., Herchenroder, O., et al. (2004). Foamy virus integration. J. Virol. 78, 2472-2477.
92. Kalpana, G. V., Marmon, S., Wang, W., Crabtree, G. R., and Goff, S. P. (1994). Binding and stimulation of HIV-1 integrase by a human homolog of yeast transcription factor SNF5. Science 266, 2002-2006.
93. Kantor, B., Ma, H., Webster-Cyriaque, J., Monahan, P. E., and Kafri, T. (2009). Epigenetic activation of unintegrated HIV-1 genomes by gut-associated short chain fatty acids and its implications for HIV infection. Proc. Natl. Acad. Sci. U.S.A. 106, 18786-18791. doi: 10.1073/Pnas.0905859106
94. Kelly, J., Beddall, M. H., Yu, D. Y., Iyer, S. R., Marsh, J. W., and Wu, Y. T. (2008). Human macrophages support persistent transcription from unintegrated HIV-1 DNA. Virology 372, 300-312. doi: 10.1016/J.Virol.2007.11.007
95. Kessl, J. J., Eidahl, J. O., Shkriabai, N., Zhao, Z. J., Mckee, C. J., Hess, S., et al. (2009). An allosteric mechanism for inhibiting HIV-1 integrase with a small molecule. Mol. Pharmacol. 76, 824-832. doi: 10.1124/Mol.109.058883
96. Kilzer, J. M., Stracker, T., Beitzel, B., Meek, K., Weitzman, M., and Bushman, F. D. (2003). Roles of host cell factors in circularization of retroviral DNA. Virology 314, 460-467. doi: 10.1016/S0042-6822(03)00455-0
97. Laboulais, C., Deprez, E., Leh, H., Mouscadet, J. F., Brochon, J. C., and Le Bret, M. (2001). HIV-1 integrase catalytic core: molecular dynamics and simulated fluorescence decays. Biophys. J. 81, 473-489.
98. Le Rouzic, E., Bonnard, D., Chasset, S., Bruneau, J. M., Chevreuil, F., Le Strat, F., et al. (2013). Dual inhibition of HIV-1 replication by integrase-LEDGF allosteric inhibitors is predominant at the post-integration stage. Retrovirology 10:144. doi: 10.1186/1742-4690-10-144
99. Leavitt, A. D., Rose, R. B., and Varmus, H. E. (1992). Both substrate and target oligonucleotide sequences affect in vitro integration mediated by human-immunodeficiency-virus type-1 integrase protein produced in Saccharomyces cerevisiae. J. Virol. 66, 2359-2368.
100. Lee, S. P., Xiao, J., Knutson, J. R., Lewis, M. S., and Han, M. K. (1997a). Zn2+ promotes the self-association of HIV-1 integrase in vitro. Biophys. J. 72, M297-M297.
101. Lee, S. P., Xiao, J. M., Knutson, J. R., Lewis, M. S., and Han, M. K. (1997b). Zn2+ promotes the self-association of human immunodeficiency virus type-1 integrase in vitro. Biochemistry 36, 173-180.
102. Leh, H., Brodin, P., Bischerour, J., Deprez, E., Tauc, P., Brochon, J. C., et al. (2000). Determinants of Mg2+-dependent activities of recombinant human immunodeficiency virus type 1 integrase. Biochemistry 39, 9285-9294. doi: 10.1021/Bi000398b
103. Lesbats, P., Metifiot, M., Calmels, C., Baranova, S., Nevinsky, G., Andreola, M. L., et al. (2008). In vitro initial attachment of HIV-1 integrase to viral ends: control of the DNA specific interaction by the oligomerization state. Nucleic Acids Res. 36, 7043-7058. doi: 10.1093/Nar/Gkn796
104. Li, L., Yoder, K., Hansen, M. S. T., Olvera, J., Miller, M. D., and Bushman, F. D. (2000). Retroviral cDNA integration: stimulation by HMG I family proteins. J. Virol. 74, 10965-10974.
105. Li, M., and Craigie, R. (2005). Processing of viral DNA ends channels the HIV-1 integration reaction to concerted integration. J. Biol. Chem. 280, 29334-29339. doi: 10.1074/Jbc.M505367200
106. Li, M., Kao, E., Gao, X., Sandig, H., Limmer, K., Pavon-Eternod, M., et al. (2012). Codon-usage-based inhibition of HIV protein synthesis by human schlafen 11. Nature 491, 125-128. doi: 10.1038/nature11433
107. Li, M., Mizuuchi, M., Burke, T. R., and Craigie, R. (2006). Retroviral DNA integration: reaction pathway and critical intermediates. EMBO J. 25, 1295-1304. doi: 10.1038/Sj.Emboj.7601005
108. Li, Y., Xuan, S., Feng, Y., and Yan, A. (2015). Targeting HIV-1 integrase with strand transfer inhibitors. Drug Discov. Today 20, 435-449. doi: 10.1016/j.drudis.2014.12.001
109. Lin, C. W., and Engelman, A. (2003). The barrier-to-autointegration factor is a component of functional human immunodeficiency virus type 1 preintegration complexes. J. Virol. 77, 5030-5036. doi: 10.1128/Jvi.77.8.5030-5036.2003
110. Llano, M., Saenz, D. T., Meehan, A., Wongthida, P., Peretz, M., Walker, W. H., et al. (2006). An essential role for LEDGF/p75 in HIV integration. Science 314, 461-464. doi: 10.1126/science.1132319
111. Low, A., Prada, N., Topper, M., Vaida, F., Castor, D., Mohri, H., et al. (2009). Natural polymorphisms of human immunodeficiency virus type 1 integrase and inherent susceptibilities to a panel of integrase inhibitors. Antimicrob. Agents Chemother. 53, 4275-4282. doi: 10.1128/Aac.00397-09
112. Maertens, G. N., Hare, S., and Cherepanov, P. (2010). The mechanism of retroviral integration from X-ray structures of its key intermediates. Nature 468, 326-329. doi: 10.1038/nature09517
113. Maes, M., Loyter, A., and Friedler, A. (2012). Peptides that inhibit HIV-1 integrase by blocking its protein-protein interactions. FEBS J. 279, 2795-2809. doi: 10.1111/j.1742-4658.2012.08680.x
114. Maignan, S., Guilloteau, J. P., Zhou-Liu, Q., Clement-Mella, C., and Mikol, V. (1998). Crystal structures of the catalytic domain of HIV-1 integrase free and complexed with its metal cofactor: high level of similarity of the active site with other viral integrases. J. Mol. Biol. 282, 359-368.
115. Maillot, B., Levy, N., Eiler, S., Crucifix, C., Granger, F., Richert, L., et al. (2013). Structural and functional role of INI1 and LEDGF in the HIV-1 preintegration complex. PLoS ONE 8:e60734. doi: 10.1371/journal.pone.0060734
116. Maldarelli, F., Palmer, S., King, M. S., Wiegand, A., Polis, M. A., Mican, J., et al. (2007). ART suppresses plasma HIV-1 RNA to a stable set point predicted by pretherapy viremia. PLOS Pathog. 3:e46. doi: 10.1371/journal.ppat.0030046
117. Malet, I., Delelis, O., Valantin, M. A., Montes, B., Soulie, C., Wirden, M., et al. (2008). Mutations associated with failure of raltegravir treatment affect integrase sensitivity to the inhibitor in vitro. Antimicrob. Agents Chemother. 52, 1351-1358. doi: 10.1128/AAC.01228-07
118. Malet, I., Gimferrer Arriaga, L., Artese, A., Costa, G., Parrotta, L., Alcaro, S., et al. (2014). New raltegravir resistance pathways induce broad cross-resistance to all currently used integrase inhibitors. J. Antimicrob. Chemother. 69, 2118-2122. doi: 10.1093/jac/dku095
119. Marchand, C. (2012). The elvitegravir Quad pill: the first once-daily dual-target anti-HIV tablet. Expert Opin. Investig. Drugs 21, 901-904. doi: 10.1517/13543784.2012.685653
120. Marinello, J., Marchand, C., Mott, B. T., Bain, A., Thomas, C. J., and Pommier, Y. (2008). Comparison of raltegravir and elvitegravir on HIV-1 integrase catalytic reactions and on a series of drug-resistant integrase mutants. Biochemistry 47, 9345-9354. doi: 10.1021/bi800791q
121. Martinez, M. A., Cabana, M., Ibanez, A., Clotet, B., Arno, A., and Ruiz, L. (1999). Human immunodeficiency virus type 1 genetic evolution in patients with prolonged suppression of plasma viremia. Virology 256, 180-187. doi: 10.1006/viro.1999.9601
122. Masuda, T., Kuroda, M. J., and Harada, S. (1998). Specific and independent recognition of U3 and U5 att sites by human immunodeficiency virus type 1 integrase in vivo. J. Virol. 72, 8396-8402.
123. Mathew, S., Nguyen, M., Wu, X., Pal, A., Shah, V. B., Prasad, V. R., et al. (2013). INI1/hSNF5-interaction defective HIV-1 IN mutants exhibit impaired particle morphology, reverse transcription and integration in vivo. Retrovirology 10:66. doi: 10.1186/1742-4690-10-66
124. Mazumder, A., Uchida, H., Neamati, N., Sunder, S., JaworskaMaslanka, M., Wickstrom, E., et al. (1997). Probing interactions between viral DNA and human immunodeficiency virus type 1 integrase using dinucleotides. Mol. Pharmacol. 51, 567-575.
125. McMahon, D., Jones, J., Wiegand, A., Gange, S. J., Kearney, M., Palmer, S., et al. (2010). Short-course raltegravir intensification does not reduce persistent low-level viremia in patients with HIV-1 suppression during receipt of combination antiretroviral therapy. Clin. Infect. Dis. 50, 912-919. doi: 10.1086/650749
126. Molina, J. M., Clotet, B., van Lunzen, J., Lazzarin, A., Cavassini, M., Henry, K., et al. (2014). Once-daily dolutegravir is superior to once-daily darunavir/ritonavir in treatment-naive HIV-1-positive individuals: 96 week results from FLAMINGO. J. Int. AIDS Soc. 17(4 Suppl. 3), 19490. doi: 10.7448/IAS.17.4.19490
127. Munir, S., Thierry, E., Malet, I., Subra, F., Calvez, V., Marcelin, A. G., et al. (2015). G118R and F121Y mutations identified in patients failing raltegravir treatment confer dolutegravir resistance. J. Antimicrob. Chemother. 70, 739-749. doi: 10.1093/jac/dku474
128. Munir, S., Thierry, S., Subra, F., Deprez, E., and Delelis, O. (2013). Quantitative analysis of the time-course of viral DNA forms during the HIV-1 life cycle. Retrovirology 10:87. doi: 10.1186/1742-4690-10-87
129. Ni, X. J., Delelis, O., Charpentier, C., Storto, A., Collin, G., Damond, F., et al. (2011). G140S/Q148R and N155H mutations render HIV-2 Integrase resistant to raltegravir whereas Y143C does not. Retrovirology 8:68. doi: 10.1186/1742-4690-8-68
130. Parissi, V., Calmels, C., De Soultrait, V. R., Caumont, A., Fournier, M., Chaignepain, S., et al. (2001). Functional interactions of human immunodeficiency virus type 1 integrase with human and yeast HSP60. J. Virol. 75, 11344-11353.
131. Park, T. E., Mohamed, A., Kalabalik, J., and Sharma, R. (2015). Review of integrase strand transfer inhibitors for the treatment of human immunodeficiency virus infection. Expert Rev. Anti Infect. Ther. 13, 1195-1212. doi: 10.1586/14787210.2015.1075393
132. Peat, T. S., Rhodes, D. I., Vandegraaff, N., Le, G., Smith, J. A., Clark, L. J., et al. (2012). Small molecule inhibitors of the LEDGF site of human immunodeficiency virus integrase identified by fragment screening and structure based design. PLoS ONE 7:e40147. doi: 10.1371/journal.pone.0040147
133. Pierson, T. C., Kieffer, T. L., Ruff, C. T., Buck, C., Gange, S. J., and Siliciano, R. F. (2002). Intrinsic stability of episomal circles formed during human immunodeficiency virus type 1 replication. J. Virol. 76, 4138-4144.
134. Pinskaya, M., Romanova, E., Volkov, E., Deprez, E., Leh, H., Brochon, J. C., et al. (2004). HIV-1 integrase complexes with DNA dissociate in the presence of short oligonucleotides conjugated to acridine. Biochemistry 43, 8735-8743. doi: 10.1021/Bi049706m
135. Quercia, R., Dam, E., Perez-Bercoff, D., and Clavel, F. (2009). Selective-advantage profile of human immunodeficiency virus type 1 integrase mutants explains in vivo evolution of raltegravir resistance genotypes. J. Virol. 83, 10245-10249. doi: 10.1128/Jvi.00894-09
136. Raffi, F., Rachlis, A., Stellbrink, H. J., Hardy, W. D., Torti, C., Orkin, C., et al. (2013). 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 381, 735-743. doi: 10.1016/S0140-6736(12)61853-4
137. Rhee, S. Y., Liu, T. F., Kiuchi, M., Zioni, R., Gifford, R. J., Holmes, S. P., et al. (2008). Natural variation of HIV-1 group M integrase: implications for a new class of antiretroviral inhibitors. Retrovirology 5:74. doi: 10.1186/1742-4690-5-74
138. Robinson, W. E., Cordeiro, M., AbdelMalek, S., Jia, Q., Chow, S. A., Reinecke, M. G., et al. (1996). Dicaffeoylquinic acid inhibitors of human immunodeficiency virus integrase: inhibition of the core catalytic domain of human immunodeficiency virus integrase. Mol. Pharmacol. 50, 846-855.
139. Sakurai, Y., Komatsu, K., Agematsu, K., and Matsuoka, M. (2009). DNA double strand break repair enzymes function at multiple steps in retroviral infection. Retrovirology 6:114. doi: 10.1186/1742-4690-6-114
140. Serrao, E., Odde, S., Ramkumar, K., and Neamati, N. (2009). Raltegravir, elvitegravir, and metoogravir: the birth of "me-too" HIV-1 integrase inhibitors. Retrovirology 6:33. doi: 10.1186/1742-4690-6-33
141. Shadrina, O., Krotova, O., Agapkina, J., Knyazhanskaya, E., Korolev, S., Starodubova, E., et al. (2014). Consensus HIV-1 subtype A integrase and its raltegravir-resistant variants: design and characterization of the enzymatic properties. Biochimie 102, 92-101. doi: 10.1016/j.biochi.2014.02.013
142. Sharkey, M. E., Teo, I., Greenough, T., Sharova, N., Luzuriaga, K., Sullivan, J. L., et al. (2000). Persistence of episomal HIV-1 infection intermediates in patients on highly active anti-retroviral therapy. Nat. Med. 6, 76-81. doi: 10.1038/71569
143. Sharma, A., Slaughter, A., Jena, N., Feng, L., Kessl, J. J., Fadel, H. J., et al. (2014). A new class of multimerization selective inhibitors of HIV-1 integrase. PLoS Pathog. 10:e1004171. doi: 10.1371/journal.ppat.1004171
144. Shimura, K., Kodama, E., Sakagami, Y., Matsuzaki, Y., Watanabe, W., Yamataka, K., et al. (2008). Broad Antiretroviral activity and resistance profile of the novel human immunodeficiency virus integrase inhibitor elvitegravir (JTK-303/GS-9137). J. Virol. 82, 764-774. doi: 10.1128/Jvi.01534-07
145. Sinha, S., and Grandgenett, D. P. (2005). Recombinant human immunodeficiency virus type 1 integrase exhibits a capacity for full-site integration in vitro that is comparable to that of purified preintegration complexes from virus-infecte cells. J. Virol. 79, 8208-8216. doi: 10.1128/Jvi.79.13.8208-8216.2005
146. Sinha, S., Pursley, M. H., and Grandgenett, D. P. (2002). Efficient concerted integration by recombinant human immunodeficiency virus type 1 integrase without cellular or viral cofactors. J. Virol. 76, 3105-3113. doi: 10.1128/Jvi.76.7.3105-3113.2002
147. Sloan, R. D., Kuhl, B. D., Donahue, D. A., Roland, A., Bar-Magen, T., and Wainberg, M. A. (2011). Transcription of preintegrated HIV-1 cDNA modulates cell surface expression of major histocompatibility complex class I via Nef. J. Virol. 85, 2828-2836. doi: 10.1128/JVI.01854-10
148. Sloan, R. D., and Wainberg, M. A. (2011). The role of unintegrated DNA in HIV infection. Retrovirology 8:52. doi: 10.1186/1742-4690-8-52
149. Sourgen, F., Maroun, R. G., Frere, V., Bouziane, M., Auclair, C., Troalen, F., et al. (1996). A synthetic peptide from the human immunodeficiency virus type-1 integrase exhibits coiled-coil properties and interferes with the in vitro integration activity of the enzyme-Correlated biochemical and spectroscopic results. Eur. J. Biochem. 240, 765-773.
150. Spreen, W. R., Margolis, D. A., and Pottage, J. C. Jr. (2013). Long-acting injectable antiretrovirals for HIV treatment and prevention. Curr. Opin. HIV AIDS 8, 565-571. doi: 10.1097/COH.0000000000000002
151. Steigbigel, R. T., Cooper, D. A., Kumar, P. N., Eron, J. E., Schechter, M., Markowitz, M., et al. (2008). Raltegravir with optimized background therapy for resistant HIV-1 infection. N. Engl. J. Med. 359, 339-354.
152. Stevenson, M., Haggerty, S., Lamonica, C. A., Meier, C. M., Welch, S. K., and Wasiak, A. J. (1990). Integration is not necessary for expression of human immunodeficiency virus type 1 protein products. J. Virol. 64, 2421-2425.
153. Summa, V., Petrocchi, A., Bonelli, F., Crescenzi, B., Donghi, M., Ferrara, M., et al. (2008). Discovery of Raltegravir, a potent, selective orally bioavailable HIV-integrase inhibitor for the treatment of HIV-AIDS infection. J. Med. Chem. 51, 5843-5855. doi: 10.1021/Jm800245z
154. Svarovskaia, E. S., Barr, R., Zhang, X., Pais, G. C., Marchand, C., Pommier, Y., et al. (2004). Azido-containing diketo acid derivatives inhibit human immunodeficiency virus type 1 integrase in vivo and influence the frequency of deletions at two-long-terminal-repeat-circle junctions. J. Virol. 78, 3210-3222.
155. Thierry, S., Munir, S., Thierry, E., Subra, F., Leh, H., Zamborlini, A., et al. (2015). Integrase inhibitor reversal dynamics indicate unintegrated HIV-1 dna initiate de novo integration. Retrovirology 12:24. doi: 10.1186/s12977-015-0153-9
156. Thierry, S., Thierry, E., Subra, F., Deprez, E., Leh, H., Bury-Mone, S., et al. (2016). Opposite transcriptional regulation of integrated vs unintegrated HIV genomes by the NF-kappaB pathway. Sci. Rep. 6:25678. doi: 10.1038/srep25678
157. Trinite, B., Ohlson, E. C., Voznesensky, I., Rana, S. P., Chan, C. N., Mahajan, S., et al. (2013). An HIV-1 replication pathway utilizing reverse transcription products that fail to integrate. J. Virol. 87, 12701-12720. doi: 10.1128/JVI.01939-13
158. Underwood, M. R., Johns, B. A., Sato, A., Martin, J. N., Deeks, S. G., and Fujiwara, T. (2012). The activity of the integrase inhibitor dolutegravir against HIV-1 variants isolated from raltegravir-treated adults. J. Acquir. Immune Defic. Syndr. 61, 297-301. doi: 10.1097/QAI.0b013e31826bfd02
159. Valkov, E., Gupta, S. S., Hare, S., Helander, A., Roversi, P., McClure, M., et al. (2009). Functional and structural characterization of the integrase from the prototype foamy virus. Nucleic Acids Res. 37, 243-255. doi: 10.1093/Nar/Gkn938
160. Vallejo, A., Gutierrez, C., Hernandez-Novoa, B., Diaz, L., Madrid, N., Abad-Fernandez, M., et al. (2012). The effect of intensification with raltegravir on the HIV-1 reservoir of latently infected memory CD4 T cells in suppressed patients. Aids 26, 1885-1894. doi: 10.1097/QAD.0b013e3283584521
161. Van Baelen, K., Van Eygen, V., Rondelez, E., and Stuyver, L. J. (2008). Clade-specific HIV-1 integrase polymorphisms do not reduce raltegravir and elvitegravir phenotypic susceptibility. AIDS 22, 1877-1880. doi: 10.1097/Qad.0b013e32830f9703
162. van den Ent, F. M. I., Vos, A., and Plasterk, R. H. A. (1999). Dissecting the role of the N-terminal domain of human immunodeficiency virus integrase by trans-complementation analysis. J. Virol. 73, 3176-3183.
163. Vandegraaff, N., and Engelman, A. (2007). Molecular mechanisms of HIV integration and therapeutic intervention. Expert Rev. Mol. Med. 9, 1-19. doi: 10.1017/S1462399407000257
164. Walmsley, S. L., Antela, A., Clumeck, N., Duiculescu, D., Eberhard, A., Gutierrez, F., et al. (2013). Dolutegravir plus abacavir-lamivudine for the treatment of HIV-1 infection. N. Engl. J. Med. 369, 1807-1818. doi: 10.1056/NEJMoa1215541
165. Wang, J. Y., Ling, H., Yang, W., and Craigie, R. (2001). Structure of a two-domain fragment of HIV-1 integrase: implications for domain organization in the intact protein. EMBO J. 20, 7333-7343.
166. Wu, Y., and Marsh, J. W. (2001). Selective transcription and modulation of resting T cell activity by preintegrated HIV DNA. Science 293, 1503-1506. doi: 10.1126/science.1061548
167. Wu, Y., and Marsh, J. W. (2003). Gene transcription in HIV infection. Microbes Infect. 5, 1023-1027.
168. Yoshinaga, T., Kobayashi, M., Seki, T., Miki, S., Wakasa-Morimoto, C., Suyama-Kagitani, A., et al. (2015). Antiviral characteristics of GSK1265744, an HIV integrase inhibitor dosed orally or by long-acting injection. Antimicrob. Agents Chemother. 59, 397-406. doi: 10.1128/AAC.03909-14
169. Zhang, D. W., He, H. Q., and Guo, S. X. (2014). Hairpin DNA probe-based fluorescence assay for detecting palindrome cleavage activity of HIV-1 integrase. Anal. Biochem. 460C, 36-38. doi: 10.1016/j.ab.2014.05.010
170. Zhang, D. W., Zhao, M. M., He, H. Q., and Guo, S. X. (2013). Real-time monitoring of disintegration activity of catalytic core domain of HIV-1 integrase using molecular beacon. Anal. Biochem. 440, 120-122. doi: 10.1016/j.ab.2013.05.032
171. Zheng, R. L., Jenkins, T. M., and Craigie, R. (1996). Zinc folds the N-terminal domain of HIV-1 integrase, promotes multimerization, and enhances catalytic activity. Proc. Natl. Acad. Sci. U.S.A. 93, 13659-13664.
172. Zouhiri, F., Mouscadet, J. F., Mekouar, K., Desmaele, D., Savoure, D., Leh, H., et al. (2000). Structure-activity relationships and binding mode of styrylquinolines as potent inhibitors of HIV-1 integrase and replication of HIV-1 in cell culture. J. Med. Chem. 43, 1533-1540.