Pleiotropic Nature of HIV-1 Integrase Mutations

HIV-1 Integrase: Mechanism and Inhibitor Design

Volumn , Issue , 2011, Pages 67-81

  Engelman, Alan ^a,b  

^a DANA FARBER CANCER INSTITUTE   (United States)

^b HARVARD MEDICAL SCHOOL   (United States)

Author keywords

HIV 1 assembly release; HIV 1 integrase function; HIV 1 integrase mutations

Indexed keywords

EID: 84873096058     PISSN: None     EISSN: None     Source Type: Book    
DOI: 10.1002/9781118015377.ch6     Document Type: Chapter

References (204)

1. Pomerantz, R. J.; Horn, D. L. Twenty years of therapy for HIV-1 infection. Nat. Med. 2003, 9, 867-873.
2. Clavel, F.; Hance, A. J. HIV drug resistance. N. Engl. J. Med. 2004, 350, 1023-1035.
3. Meanwell, N. A.; Kadow, J. F. Maraviroc, a chemokine CCR5 receptor antagonist for the treatment of HIV infection and AIDS. Curr. Opin. Investig. Drugs 2007, 8, 669-681.
4. Evering, T. H.; Markowitz, M. Raltegravir (MK-0518): An integrase inhibitor for the treatment of HIV-1. Drugs Today (Barc.) 2007, 43, 865-877.
5. Engelman, A.; Cherepanov, P. Recent advances in retroviral replication: Cellular machines and novel anti-viral defense mechanisms. In Recent Advances in RNA Virus Replication (K. L. Hefferon, Ed.) Transworld Research Network, Kerala, India, 2006, pp. 91-129.
6. Jones, R.; Nelson, M. The role of receptors in the HIV-1 entry process. Eur. J. Med. Res. 2007, 12, 391-396.
7. Karageorgos, L.; Li, P.; Burrel, C. Characterization of HIV replication complexes early after cell-to-cell infection. AIDS Res. Hum. Retroviruses 1993, 9, 817-823.
8. Fassati, A.; Goff, S. P. Characterization of intracellular reverse transcription complexes of human immunodeficiency virus type 1. J. Virol. 2001, 75, 3626-3635.
9. McDonald, D.; Vodicka, M. A.; Lucero, G.; Svitkina, T. M.; Borisy, G. G.; Emerman, M.; Hope, T. J. Visualization of the intracellular behavior of HIV in living cells. J. Cell Biol. 2002, 159, 441-452.
10. Arhel, N.; Genovesio, A.; Kim, K. A.; Miko, S.; Perret, E.; Olivo-Marin, J. C.; Shorte, S.; Charneau, P. Quantitative fourdimensional tracking of cytoplasmic and nuclear HIV-1 complexes. Nat. Methods 2006, 3, 817-824.
11. Engelman, A.; Mizuuchi, K.; Craigie, R. HIV-1 DNA integration: Mechanism of viral DNA cleavage and DNA strand transfer. Cell 1991, 67, 1211-1221.
12. Faure, A.; Calmels, C.; Desjobert, C.; Castroviejo, M.; Caumont-Sarcos, A.; Tarrago-Litvak, L.; Litvak, S.; Parissi, V. HIV-1 integrase crosslinked oligomers are active in vitro. Nucleic Acids Res. 2005. 33, 977-986.
13. Guiot, E.; Carayon, K.; Delelis, O.; Simon, F.; Tauc, P.; Zubin, E.; Gottikh, M.; Mouscadet, J.-F.; Brochon, J.-C.; Deprez, E. Relationship between the oligomeric status of HIV-1 integrase on DNA and enzymatic activity. J. Biol. Chem. 2006, 281, 22707-22719.
14. Li, M.; Mizuuchi, M.; Burke, T. R., Jr.; Craigie, R. Retroviral DNA integration: Reaction pathway and critical intermediates. EMBO J. 2006, 25, 1295-1304.
15. Miller, M.; Farnet, C.; Bushman, F. Human immunodeficiency virus type 1 preintegration complexes: Studies of organization and composition. J. Virol. 1997, 71, 5382-5390.
16. Wei, S.-Q.; Mizuuchi, K.; Craigie, R. A large nucleoprotein assembly at the ends of the viral DNA mediates retroviral DNA integration. EMBO J. 1997, 16, 7511-7520.
17. Wei, S.-Q.; Mizuuchi, K.; Craigie, R. Footprints on the viral DNA ends in Moloney murine leukemia virus preintegration complexes reflect a specific association with integrase. Proc. Natl. Acad. Sci. USA 1998, 95, 10535-10540.
18. Chen, H.; Wei, S.-Q.; Engelman, A. Multiple integrase functions are required to form the native structure of the human immunodeficiency virus type I intasome. J. Biol. Chem. 1999, 274, 17358-17364.
19. Chen, H.; Engelman, A. Asymmetric processing of human immunodeficiency virus type 1 cDNA in vivo: Implications for functional end coupling during the chemical steps of DNA transposition. Mol. Cell. Biol. 2001, 21, 6758-6767.
20. Chen, H.; Engelman, A. Characterization of a replicationdefective human immunodeficiency virus type 1 att site mutant that is blocked after the 30 processing step of retroviral integration. J. Virol. 2000, 74, 8188-8193.
21. Bukrinsky, M.; Sharova, N.; Dempsey, M.; Stanwick, T.; Bukrinskaya, A.; Haggerty, S.; Stevenson, M. Active nuclear import of human immunodeficiency virus type 1 preintegration complexes. Proc. Natl. Acad. Sci. USA 1992, 89, 6580-6584.
22. Katz, R. A.; Greger, J. G.; Boimel, P.; Skalka, A. M. Human immunodeficiency virus type 1 DNA nuclear import and integration are mitosis independent in cycling cells. J. Virol. 2003, 77, 13412-13417.
23. Fassati, A. HIV infection of non-dividing cells: A divisive problem. Retrovirology 2006, 3, 74.
24. Yamashita, M.; Emerman, M. Retroviral infection of nondividing cells: Old and new perspectives. Virology 2006, 344, 88-93.
25. 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.
26. Maertens, G.; Cherepanov, P.; Pluymers, W.; Busschots, K.; De Clercq, E.; Debyser, Z.; Engelborghs, Y. LEDGF/p75 is essential for nuclear and chromosomal targeting of HIV-1 integrase in human cells. J. Biol. Chem. 2003, 278, 33528-33539.
27. Cherepanov, P.; Devroe, E.; Silver, P. A.; Engelman, A. Identification of an evolutionarily-conserved domain in LEDGF/p75 that binds HIV-1 integrase. J. Biol. Chem. 2004, 279, 48883-48892.
28. Cherepanov, P.; Ambrosio, A. L. B.; Rahman, S.; Ellenberger, T.; Engelman, A. From the Cover: Structural basis for the recognition between HIV-1 integrase and transcriptional coactivator p75. Proc. Natl. Acad. Sci. USA 2005, 102, 17308-17313.
29. Vanegas, M.; Llano, M.; Delgado, S.; Thompson, D.; Peretz, M.; Poeschla, E. Identification of the LEDGF/p75 HIV-1 integrase-interaction domain and NLS reveals NLSindependent chromatin tethering. J. Cell Sci. 2005, 118, 1733-1743.
30. Ciuffi, A.; Llano, M.; Poeschla, E.; Hoffmann, C.; Leipzig, J.; Shinn, P.; Ecker, J. R.; Bushman, F. A role for LEDGF/p75 in targeting HIV DNA integration. Nat. Med. 2005. 11, 1287-1289.
31. Llano, M.; Saenz, D. T.; Meehan, A.; Wongthida, P.; Peretz, M.; Walker, W. H.; Teo, W.; Poeschla, E. M. An essential role for LEDGF/p75 in HIV integration. Science 2006, 314, 461-464.
32. Marshall, H. M.; Ronen, K.; Berry, C.; Llano, M.; Sutherland, H.; Saenz, D.; Bickmore, W.; Poeschla, E.; Bushman, F. D. Role of PSIP1/LEDGF/p75 in lentiviral infectivity and integration targeting. PLoS ONE 2007, 2, e1340.
33. Shun, M.-C.; Raghavendra, N. K.; Vandegraaff, N.; Daigle, J. E.; 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.
34. Brin, E.; Yi, J.; Skalka, A. M.; Leis, J. Modeling the late steps in HIV-1 retroviral integrase-catalyzed DNA integration. J. Biol. Chem. 2000, 275, 39287-39295.
35. Yoder, K. E.; Bushman, F. D. Repair of gaps in retroviral DNA integration intermediates. J. Virol. 2000, 74, 11191-11200.
36. Turlure, F.; Devroe, E.; Silver, P. A.; Engelman, A. Human cell proteins and human immunodeficiency virus DNA integration. Front. Biosci. 2004, 9, 3187-3208.
37. Guntaka, R. V.; Richards, O. C.; Shank, P. R.; Kung, H.-J.; Davidson, N.; Pritsch, E.; Bishop, J. M.; Varmus, H. E. Covalently closed circular DNA of avian sarcoma virus: Purification from nuclei of infected quail tumor cells and measurement by electron microscopy and gel electrophoresis. J. Mol. Biol. 1976, 106, 337-357.
38. Brown, P. O.; Bowerman, B.; Varmus, H. E.; Bishop, J. M. Correct integration of retroviral DNA in vitro. Cell 1987, 49, 347-356.
39. Pereira, L. A.; Bentley, K.; Peeters, A.; Churchill, M. J.; Deacon, N. J. Survey and Summary: A compilation of cellular transcription factor interactions with the HIV-1 LTR promoter. Nucleic Acids Res. 2000, 28, 663-668.
40. Nekhai, S.; Jeang, K. T. Transcriptional and post-transcriptional regulation of HIV-1 gene expression: Role of cellular factors for Tat and Rev. Future Microbiol. 2006, 1, 417-426.
41. D'Souza, V.; Summers, M. F. How retroviruses select their genomes. Nat. Rev. Microbiol. 2005, 3, 643-655.
42. Garrus, J. E.; von Schwedler, U. K.; Pornillos, O. W.; Morham, S. G.; Zavitz, K. H.; Wang, H. E.; Wettstein, D. A.; Stray, K. M.; Cote,M.; Rich, R. L.; Myszka, D. G.; Sundquist, W. I. Tsg101 and the vacuolar protein sorting pathway are essential for HIV-1 budding. Cell 2001, 107, 55-65.
43. VerPlank, L.; Bouamr, F.; LaGrassa, T. J.; Agresta, B.; Kikonyogo, A.; Leis, J.; Carter, C. A. Tsg101, a homologue of ubiquitin-conjugating (E2) enzymes, binds the L domain in HIV type 1 Pr55Gag. Proc. Natl. Acad. Sci. USA 2001, 98, 7724-7729.
44. Martin-Serrano, J.; Zang, T.; Bieniasz, P. D. HIV-1 and Ebola virus encode small peptide motifs that recruit Tsg101 to sites of particle assembly to facilitate egress. Nat. Med. 2001, 7, 1313-1319.
45. Strack, B.; Calistri, A.; Craig, S.; Popova, E.; Gottlinger, H. G. AIP1/ALIX is a binding partner for HIV-1 p6 and EIAV p9 functioning in virus budding. Cell 2003, 114, 689-699.
46. Bieniasz, P. D. Late budding domains and host proteins in enveloped virus release. Virology 2006, 344, 55-63.
47. Jacks, T.; Power, M. D.; Masiarz, F. R.; Luciw, P. A.; Barr, P. J.; Varmus, H. E. Characterization of ribosomal frameshifting in HIV-1 gag-pol expression. Nature 1988, 331, 280-283.
48. Adamson, C. S.; Freed, E. O. Human immunodeficiency virus type 1 assembly, release, and maturation. Adv. Pharmacol. 2007, 55, 347-387.
49. Engelman, A.; Craigie, R. Identification of conserved amino acid residues critical for human immunodeficiency virus type 1 integrase function in vitro. J. Virol. 1992, 66, 6361-6369.
50. Bushman, F. D.; Engelman, A.; Palmer, I.; Wingfield, P.; Craigie, R. Domains of the integrase protein of human immunodeficiency virus type 1 responsible for polynucleotidyl transfer and zinc binding. Proc. Natl. Acad. Sci. USA 1993, 90, 3428-3432.
51. Engelman, A.; Bushman, F. D.; Craigie, R. Identification of discrete functional domains of HIV-1 integrase and their organization within an active multimeric complex. EMBO J. 1993, 12, 3269-3275.
52. van Gent, D. C.; Vink, C.; Groeneger, A. A. M. O.; Plasterk, R. H. A. Complementation between HIV integrase proteins mutated in different domains. EMBO J. 1993, 12, 3261-3267.
53. Vink, C.; Oude Groeneger, A. M.; Plasterk, R. H. A. Identification of the catalytic and DNA-binding region of the human immunodeficiency virus type I integrase protein. Nucleic Acids Res. 1993, 21, 1419-1425.
54. Cai, M.; Zheng, R.; Caffrey, M.; Craigie, R.; Clore, G. M.; Gronenborn, A. M. Solution structure of the N-terminal zinc binding domain of HIV-1 integrase. Nat. Struct. Biol. 1997, 4, 567-577.
55. Eijkelenboom, A. P.; van den Ent, F. M.; Vos, A.; Doreleijers, J. F.; Hard, K.; Tullius, T. D.; Plasterk, R. H.; Kaptein, R.; Boelens, R. The solution structure of the aminoterminal HHCC domain of HIV-2 integrase: A three-helix bundle stabilized by zinc. Curr. Biol. 1997, 7, 739-746.
56. Lee, S. P.; Han, M. K. Zinc stimulates Mg2{thorn} -dependent 30-processing activity of human immunodeficiency virus type 1 integrase in vitro. Biochemistry 1996, 35, 3837-3844.
57. Zheng, R.; Jenkins, T. M.; Craigie, R. Zinc folds the Nterminal domain of HIV-1 integrase, promotes multimerization, and enhances catalytic activity. Proc. Natl. Acad. Sci. USA 1996, 93, 13659-13664.
58. Lee, S. P.; Xiao, J.; Knutson, J. R.; Lewis, M. S.; Han, M. K. Zn2{thorn} promotes the self-association of human immunodeficiency virus type-1 integrase in vitro. Biochemistry 1997, 36, 173-180.
59. van den Ent, F. M. I.; Vos, A.; Plasterk, R. H. A. Dissecting the role of the N-terminal domain of human immunodeficiency virus integrase by trans-complementation analysis. J. Virol. 1999, 73, 3176-3183.
60. Zhao, Z.; McKee, C. J.; Kessl, J. J.; Santos, W. L.; Daigle, J. E.; Engelman, A.; Verdine, G.; Kvaratskhelia, M. Subunitspecific protein footprinting reveals significant structural rearrangements and a role for N-terminal Lys-14 of HIV-1 integrase during viral DNA binding. J. Biol. Chem. 2008, 283, 5632-5641.
61. Grobler, J. A.; Stillmock, K.; Hu, B.; Witmer, M.; Felock, P.; Espeseth, A. S.; Wolfe, A.; Egbertson, M.; Bourgeois, M.; Melamed, J.; Wai, J. S.; Young, S.; Vacca, J.; Hazuda, D. J. Diketo acid inhibitor mechanism and HIV-1 integrase: Implications for metal binding in the active site of phosphotransferase enzymes. Proc. Natl. Acad. Sci. USA 2002, 99, 6661-6666.
62. Garvey, E. P.; Johns, B. A.; Gartland, M. J.; Foster, S. A.; Miller, W. H.; Ferris, R. G.; Hazen, R. J.; Underwood, M. R.; Boros, E. E.; Thompson, J. B.; Weatherhead, J. G.; Koble, C. S.; Allen, S. H.; Schaller, L. T.; Sherrill, R. G.; Yoshinaga, T.; Kobayashi, M.; Wakasa-Morimoto, C.; Miki, S.; Nakahara, K.; Noshi, T.; Sato, A.; Fujiwara, T. The naphthyridinone GSK364735 is a novel, potent human immunodeficiency virus-1 integrase inhibitor and antiretroviral. Antimicrob. Agents Chemother. 2008, 52, 901-908.
63. Shimura, K.; Kodama, E.; Sakagami, Y.; Matsuzaki, Y.; Watanabe, W.; Yamataka, K.; Watanabe, Y.; Ohata, Y.; Doi, S.; Sato, M.; Kano, M.; Ikeda, S.; Matsuoka, M. Broad antiretroviral activity and resistance profile of the novel human immunodeficiency virus integrase inhibitor elvitegravir (JTK-303/GS-9137). J. Virol. 2008, 82, 764-774.
64. Malet, I.; Delelis, O.; Valantin, M.-A.; Montes, B.; Soulie, C.; Wirden, M.; Tchertanova, L.; Peytavin, G.; Reynes, J.; Mouscadet, J.-F.; Katlama, C.; Calvez, V.; Marcelin, A.-G. Mutations associated with failure of raltegravir treatment affect integrase sensitivity to the inhibitor in vitro. Antimicrob. Agents Chemother. 2008, 52, 1351-1358.
65. Drelich, M.;Wilhelm, R.;Mous, J. Identification of amino acid residues critical for endonuclease and integration activities of HIV-1 IN protein in vitro. Virology 1992, 188, 459-468.
66. Kulkosky, J.; Jones, K. S.; Katz, R. A.; Mack, J. P.; Skalka, A. M. Residues critical for retroviral integrative recombination in a region that is highly conserved among retroviral/retrotransposon integrases and bacterial insertion sequence transposases. Mol. Cell. Biol. 1992, 12, 2331-2338.
67. van Gent, D. C.; Groeneger, A. A. M. O.; Plasterk, R. H. A. Mutational analysis of the integrase protein of human immunodeficiency virus type 2. Proc. Natl. Acad. Sci. USA 1992, 89, 9598-9602.
68. Leavitt, A. D.; Shiue, L.; Varmus, H. E. Site-directed mutagenesis of HIV-1 integrase demonstrates differential effects on integrase functions in vitro. J. Biol. Chem. 1993, 268, 2113-2119.
69. Dyda, F.; Hickman, A. B.; Jenkins, T. M.; Engelman, A.; Craigie, R.; Davies, D. R. Crystal structure of the catalytic domain of HIV-1 integrase: Similarity to other polynucleotidyl transferases. Science 1994, 266, 1981-1986.
70. Chen, J. C.-H.; Krucinski, J.; Miercke, L. J. W.; Finer-Moore, J. S.; Tang, A. H.; Leavitt, A. D.; Stroud, R. M. Crystal structure of the HIV-1 integrase catalytic core and C-terminal domains: A model for viral DNA binding. Proc. Natl. Acad. Sci. USA 2000, 97, 8233-8238.
71. Wang, J.-Y.; Ling, H.; Yang, W.; Craigie, R. Structure of a two-domain fragment of HIV-1 integrase: Implications for domain organization in the intact protein. EMBO J. 2001, 20, 7333-7343.
72. Du, Z.; Ilyinskii, P. O.; Lally, K.; Desrosiers, R. C.; Engelman, A. A mutation in integrase can compensate for mutations in the simian immunodeficiency virus att site. J. Virol. 1997, 71, 8124-8132.
73. Gerton, J. L.; Brown, P. O. The core domain of HIV-1 integrase recognizes key features of its DNA substrates. J. Biol. Chem. 1997, 272, 25809-25815.
74. Heuer, T. S.; Brown, P. O. Mapping features of HIV-1 integrase near selected sites on viral and target DNA molecules in an active enzyme-DNA complex by photo-crosslinking. Biochemistry 1997, 36, 10655-10665.
75. Jenkins, T. M.; Esposito, D.; Engelman, A.; Craigie, R. Critical contacts between HIV-1 integrase and viral DNA identified by structure-based analysis and photo-crosslinking. EMBO J. 1997, 16, 6849-6859.
76. Esposito, D.; Craigie, R. Sequence specificity of viral end DNA binding by HIV-1 integrase reveals critical regions for protein-DNA interaction. EMBO J. 1998, 17, 5832-5843.
77. Gerton, J. L.; Ohgi, S.; Olsen, M.; DeRisi, J.; Brown, P. O. Effects of mutations in residues near the active site of human immunodeficiency virus type 1 integrase on specific enzyme-substrate interactions. J. Virol. 1998, 72, 5046-5055.
78. Chen, A.;Weber, I. T.; Harrison, R.W.; Leis, J. Identification of amino acids in HIV-1 and avian sarcoma virus integrase subsites required for specific recognition of the long terminal repeat ends. J. Biol. Chem. 2006, 281, 4173-4182.
79. Johnson, A. A.; Santos, W.; Pais, G. C. G.; Marchand, C.; Amin, R.; Burke, T. R., Jr.,; Verdine, G.; Pommier, Y. Integration requires a specific interaction of the donor DNA terminal 5'-cytosine with glutamine 148 of the HIV-1 integrase flexible loop. J. Biol. Chem. 2006, 281, 461-467.
80. Appa, R. S.; Shin, C.-G.; Lee, P.; Chow, S. A. Role of the nonspecific DNA-binding region and alpha helices within the core domain of retroviral integrase in selecting target DNA sites for integration. J. Biol. Chem. 2001, 276, 45848-45855.
81. Dirac, A. M. G.; Kjems, J. Mapping DNA-binding sites of HIV-1 integrase by protein footprinting. Eur. J. Biochem. 2001, 268, 743-751.
82. Harper, A. L.; Skinner, L. M.; Sudol, M.; Katzman, M. Use of patient-derived human immunodeficiency virus type 1 integrases to identify a protein residue that affects target site selection. J. Virol. 2001, 75, 7756-7762.
83. Diamond, T. L.; Bushman, F. D. Division of labor within human immunodeficiency virus integrase complexes: Determinants of catalysis and target DNA capture. J. Virol. 2005, 79, 15376-15387.
84. Lu, R.; Limon, A.; Ghory, H. Z.; Engelman, A. Genetic analyses of DNA-binding mutants in the catalytic core domain of human immunodeficiency virus type 1 integrase. J. Virol. 2005, 79, 2493-2505.
85. Jenkins, T. M.; Engelman, A.; Ghirlando, R.; Craigie, R. A soluble active mutant of HIV-1 integrase: Involvement of both the core and the C-terminal domains in multimerization. J. Biol. Chem. 1996, 271, 7712-7718.
86. Puras Lutzke, R. A.; Plasterk, R. H. A. Structure-based mutational analysis of the C-terminal DNA-binding domain of human immunodeficiency virus type 1 integrase: Critical residues for protein oligomerization and DNA binding. J. Virol. 1998, 72, 4841-4848.
87. Gao, K.; Butler, S. L.; Bushman, F. Human immunodeficiency virus type 1 integrase: Arrangement of protein domains in active cDNA complexes. EMBO J. 2001, 20, 3565-3576.
88. Woerner, A. M.; Klutch, M.; Levin, J. G.; Marcus-Sekura, C. J. Localization of DNA binding activity of HIV-1 integrase to the C-terminal half of the protein. AIDS Res. Hum. Retroviruses 1992, 8, 297-304.
89. Woerner, A. M.; Marcus-Sekura, C. J. Characterization of a DNA binding domain in the C-terminus of HIV-1 integrase by deletion mutagenesis. Nucleic Acids Res. 1993, 21, 3507-3511.
90. Engelman, A.; Hickman, A. B.; Craigie, R. The core and carboxyl-terminal domains of the integrase protein of human immunodeficiency virus type 1 each contribute to nonspecific DNA binding. J. Virol. 1994, 68, 5911-5917.
91. Puras Lutzke, R. A.; Vink, C.; Plasterk, R. H. A. Characterization of the minimal DNA-binding domain of the HIV integrase protein. Nucleic Acids Res. 1994, 22, 4125-4131.
92. Donehower, L. A.; Varmus, H. E. A mutant murine leukemia virus with a single missense codon in pol is defective in a function affecting integration. Proc. Natl. Acad. Sci. USA 1984, 81, 6461-6465.
93. Schwartzberg, P.; Colicelli, J.; Goff, S. P. Construction and analysis of deletion mutations in the pol gene of moloney murine leukemia virus: A new viral function required for productive infection. Cell 1984, 37, 1043-1052.
94. Panganiban, A. T.; Temin, H. M. The retrovirus pol gene encodes a product required for DNA integration: Identification of a retrovirus int locus. Proc. Natl. Acad. Sci. USA 1984, 81, 7885-7889.
95. Stevenson, M.; Haggerty, S.; Lamonica, C. A.; Meier, C. M.; Welch, S. K.; Wasiak, A. J. Integration is not necessary for expression of human immunodeficiency virus type 1 protein products. J. Virol. 1990, 64, 2421-2425.
96. Adachi, A.; Ono, N.; Sakai, H.; Ogawa, K.; Shibata, R.; Kiyomasu, T.; Masuike, H.; Ueda, S. Generation and characterization of the human immunodeficiency virus type 1 mutants. Arch. Virol. 1991, 117, 45-58.
97. Engelman, A. In vivo analysis of retroviral integrase structure and function. Adv. Virus Res. 1999, 52, 411-426.
98. Fujiwara, T.; Mizuuchi, K. Retroviral DNA integration: Structure of an integration intermediate. Cell 1988, 54, 497-504.
99. Brown, P. O.; Bowerman, B.; Varmus, H. E.; Bishop, J. M. Retroviral integration: Structure of the initial covalent product and its precursor, and a role for the viral IN protein. Proc. Natl. Acad. Sci. USA 1989, 86, 2525-2529.
100. Lobel, L. I.; Murphy, J. E.; Goff, S. P. The palindromic LTRLTR junction of Moloney murine leukemia virus is not an efficient substrate for proviral integration. J. Virol. 1989, 63, 2629-2637.
101. Lee, Y. M.; Coffin, J. M. Relationship of avian retrovirus DNA synthesis to integration in vitro. Mol. Cell Biol. 1991, 11, 1419-1430.
102. LaFemina, R.; Schneider, C.; Robbins, H.; Callahan, P.; LeGrow, K.; Roth, E.; Schleif, W.; Emini, E. Requirement of active human immunodeficiency virus type 1 integrase enzyme for productive infection of human T-lymphoid cells. J. Virol. 1992, 66, 7414-7419.
103. Cannon, P. M.; Wilson, W.; Byles, E. D.; Kingsman, S. M.; Kingsman, A. J. Human immunodeficiency virus type 1 integrase: Effect on viral replication of mutations at highly conserved residues. J. Virol. 1994, 68, 4768-4775.
104. Shin, C.; Taddeo, B.; Haseltine, W.; Farnet, C. Genetic analysis of the human immunodeficiency virus type 1 integrase protein. J. Virol. 1994, 68, 1633-1642.
105. Taddeo, B.; Haseltine, W.; Farnet, C. Integrase mutants of human immunodeficiency virus type 1 with a specific defect in integration. J. Virol. 1994, 68, 8401-8405.
106. Ansari-Lari, M. A.; Donehower, L. A.; Gibbs, R. Analysis of human immunodeficiency virus type 1 integrase mutants. Virology 1995, 211, 332-335.
107. Engelman, A.; Englund, G.; Orenstein, J. M.; Martin, M. A.; Craigie, R. Multiple effects of mutations in human immunodeficiency virus type 1 integrase on viral replication. J. Virol. 1995, 69, 2729-2736.
108. Masuda, T.; Planelles, V.; Krogstad, P.; Chen, I. S. Genetic analysis of human immunodeficiency virus type 1 integrase and the U3 att site: Unusual phenotype of mutants in the zinc finger-like domain. J. Virol. 1995, 69, 6687-6696.
109. Wiskerchen, M.; Muesing, M. A. Human immunodeficiency virus type 1 integrase: Effects of mutations on viral ability to integrate, direct viral gene expression from unintegrated viral DNA templates, and sustain viral propagation in primary cells. J. Virol. 1995, 69, 376-386.
110. Leavitt,A.D.; Robles, G.; Alesandro, N.;Varmus,H.E.Human immunodeficiency virus type1 integrase mutants retain invitro integrase activity yet fail to integrate viral DNA efficiently during infection. J. Virol. 1996, 70, 721-728.
111. Wu, Y.; Marsh, J. W. Early transcription from nonintegrated DNA in human immunodeficiency virus infection. J. Virol. 2003, 77, 10376-10382.
112. Li, L.; Olvera, J. M.; Yoder, K. E.; Mitchell, R. S.; Butler, S. L.; Lieber, M.; Martin, S. L.; Bushman, F. D. Role of the non-homologous DNA end joining pathway in the early steps of retroviral infection. EMBO J. 2001, 20, 3272-3281.
113. Kilzer, J. M.; Stracker,T.; Beitzel, B.;Meek, K.;Weitzman, M.; Bushman, F. D. Roles of host cell factors in circularization of retroviral DNA. Virology 2003, 314, 460-467.
114. Cara, A.; Cereseto, A.; Lori, F.; Reitz, M. S., Jr., HIV-1 protein expression from synthetic circles of DNA mimicking the extrachromosomal forms of viral DNA. J. Biol. Chem. 1996, 271, 5393-5397.
115. Brussel, A.; Sonigo, P. Evidence for gene expression by unintegrated human immunodeficiency virus type 1 DNA species. J. Virol. 2004, 78, 11263-11271.
116. Kelly, J.; Beddall, M. H.; Yu, D.; Iyer, S. R.; Marsh, J. W.; Wu, Y. Human macrophages support persistent transcription from unintegrated HIV-1 DNA. Virology 2008, 372, 300-312.
117. Wu, Y.; Marsh, J. W. Selective transcription and modulation of resting T cell activity by preintegrated HIV DNA. Science 2001, 293, 1503-1506.
118. Roth, M. J.; Schwartzberg, P. L.; Goff, S. P. Structure of the termini of DNA intermediates in the integration of retroviral DNA: Dependence on IN function and terminal DNA sequence. Cell 1989, 58, 47-54.
119. Roth, M. J.; Schwartzberg, P.; Tanese, N.; Goff, S. P. Analysis of mutations in the integration function of Moloney murine leukemia virus: Effects on DNA binding and cutting. J. Virol. 1990, 64, 4709-4717.
120. Panganiban, A. T.; Temin, H. M. The terminal nucleotides of retrovirus DNA are required for integration but not virus production. Nature 1983, 306, 155-160.
121. Hazuda, D. J.; Felock, P.; Witmer, M.; Wolfe, A.; Stillmock, K.; Grobler, J. A.; Espeseth, A.; Gabryelski, L.; Schleif, W.; Blau, C.; Miller, M. D. Inhibitors of strand transfer that prevent integration and inhibit HIV-1 replication in cells. Science 2000, 287, 646-650.
122. Kehlenbeck, S.; Betz, U.; Birkmann, A.; Fast, B.; Goller, A. H.; Henninger, K.; Lowinger, T.; Marrero, D.; Paessens, A.; Paulsen, D.; Pevzner, V.; Schohe-Loop, R.; Tsujishita, H.; Welker, R.; Kreuter, J.; Rubsamen-Waigmann, H.; Dittmer, F. Dihydroxythiophenes are novel potent inhibitors of human immunodeficiency virus integrase with a diketo acid-like pharmacophore. J. Virol. 2006, 80, 6883-6894.
123. Hazuda, D. J.; Anthony, N. J.; Gomez, R. P.; Jolly, S. M.;Wai, J. S.; Zhuang, L.; Fisher, T. E.; Embrey, M.; Guare, J. P., Jr.; Egbertson, M. S.; Vacca, J. P.; Huff, J. R.; Felock, P. J.; Witmer, M. V.; Stillmock, K. A.; Danovich, R.; Grobler, J.; Miller, M. D.; Espeseth, A. S.; Jin, L.; Chen, I.W.; Lin, J. H.; Kassahun, K.; Ellis, J. D.; Wong, B. K.; Xu, W.; Pearson, P. G.; Schleif, W. A.; Cortese, R.; Emini, E.; Summa, V.; Holloway, M. K.; Young, S. D. A naphthyridine carboxamide provides evidence for discordant resistance between mechanistically identical inhibitors of HIV-1 integrase. Proc. Natl. Acad. Sci. USA 2004, 101, 11233-11238.
124. Hazuda, D. J.; Young, S. D.; Guare, J. P.; Anthony, N. J.; Gomez, R. P.;Wai, J. S.; Vacca, J. P.; Handt, L.; Motzel, S. L.; Klein, H. J.; Dornadula, G.; Danovich, R. M.;Witmer, M. V.; Wilson, K. A.; Tussey, L.; Schleif, W. A.; Gabryelski, L. S.; Jin, L.; Miller, M. D.; Casimiro, D. R.; Emini, E. A.; Shiver, J. W. Integrase inhibitors and cellular immunity suppress retroviral replication in rhesus macaques. Science 2004, 305, 528-532.
125. Cannon, P. M.; Byles, E. D.; Kingsman, S. M.; Kingsman, A. J. Conserved sequences in the carboxyl terminus of integrase that are essential for human immunodeficiency virus type 1 replication. J. Virol. 1996, 70, 651-657.
126. Li, M.; Craigie, R. Processing of viral DNA ends channels the HIV-1 integration reaction to concerted integration. J. Biol. Chem. 2005, 280, 29334-29339.
127. Cockrell, A. S.; Kafri, T. Gene delivery by lentivirus vectors. Mol. Biotechnol. 2007, 36, 184-204.
128. Nakajima, N.; Lu, R.; Engelman, A. Human immunodeficiency virus type 1 replication in the absence of integrasemediated DNA recombination: Definition of permissive and nonpermissive T-cell lines. J. Virol. 2001, 75, 7944-7955.
129. Lu, R.; Limón, A.; Devroe, E.; Silver, P. A.; Cherepanov, P.; Engelman, A. Class II integrase mutants with changes in putative nuclear localization signals are primarily blocked at a post-nuclear entry step of human immunodeficiency virus type 1 replication. J. Virol. 2004, 78, 12735-12746.
130. Nightingale, S. J.; Hollis, R. P.; Pepper, K. A.; Petersen, D.; Yu, X. J.; Yang, C.; Bahner, I.; Kohn, D. B. Transient gene expression by nonintegrating lentiviral vectors. Mol. Ther. 2006, 13, 1121-1132.
131. Y-an{ogonek}ez-Mun{ogonek}oz, R. J.; Balaggan, K. S.; MacNeil, A.; Howe, S. J.; Schmidt, M.; Smith, A. J.; Buch, P.; MacLaren, R. E.; Anderson, P. N.; Barker, S. E.; Duran, Y.; Bartholomae, C.; von Kalle, C.; Heckenlively, J. R.; Kinnon, C.; Ali, R. R.; Thrasher, A. J. Effective gene therapy with nonintegrating lentiviral vectors. Nat. Med. 2006, 12, 348-353.
132. Apolonia, L.; Waddington, S. N.; Fernandes, C.; Ward, N. J.; Bouma, G.; Blundell, M. P.; Thrasher, A. J.; Collins, M. K.; Philpott, N. J. Stable gene transfer to muscle using nonintegrating lentiviral vectors. Mol. Ther. 2007, 15, 1947-1954.
133. Kimpton, J.; Emerman, M. Detection of replicationcompetent and pseudotyped human immunodeficiency virus with a sensitive cell line on the basis of activation of an integrated beta-galactosidase gene. J. Virol. 1992, 66, 2232-2239.
134. Engelman, A.; Liu, Y.; Chen, H.; Farzan, M.; Dyda, F. Structure-based mutagenesis of the catalytic domain of human immunodeficiency virus type 1 integrase. J. Virol. 1997, 71, 3507-3514.
135. Gaur, M.; Leavitt, A. D. Mutations in the human immunodeficiency virus type 1 integrase D, D(35)E motif do not eliminate provirus formation. J. Virol. 1998, 72, 4678-4685.
136. DeJesus, E.; Berger, D.; Markowitz, M.; Cohen, C.; Hawkins, T.; Ruane, P.; Elion, R.; Farthing, C.; Zhong, L.; Cheng, A. K.; McColl, D.; Kearney, B. P. Antiviral activity, pharmacokinetics, and dose response of the HIV-1 integrase inhibitor GS-9137 (JTK-303) in treatment-naive and treatment-experienced patients. J. Acquir. Immune Defic. Syndr. 2006, 43, 1-5.
137. Markowitz, M.; Morales-Ramirez, J. O.; Nguyen, B. Y.; Kovacs, C. M.; Steigbigel, R. T.; Cooper, D. A.; Liporace, R.; Schwartz, R.; Isaacs, R.; Gilde, L. R.; Wenning, L.; Zhao, J.; Teppler, H. Antiretroviral activity, pharmacokinetics, and tolerability of MK-0518, a novel inhibitor of HIV-1 integrase, dosed as monotherapy for 10 days in treatmentnaive HIV-1-infected individuals. J. Acquir. Immune Defic. Syndr. 2006, 43, 509-515.
138. Markowitz, M.; Nguyen, B. Y.; Gotuzzo, E.; Mendo, F.; Ratanasuwan, W.; Kovacs, C.; Prada, G.; Morales-Ramirez, J. O.; Crumpacker, C. S.; Isaacs, R. D.; Gilde, L. R.;Wan, H.; Miller, M. D.; Wenning, L. A.; Teppler, H.; Team., P. P. I. S. 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, 125-133.
139. Grinsztejn, B.; Nguyen, B.-Y.; Katlama, C.; Gatell, J. M.; Lazzarin, A.; Vittecoq, D.; Gonzalez, C. J.; Chen, J.; Harvey, C. M.; Isaacs, R. D. 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 2007, 369, 1261-1269.
140. Reddy, Y. S.; Min, S. S.; Borland, J.; Song, I.; Lin, J.; Palleja, S.; Symonds, W. T. Safety and pharmacokinetics of GSK364735, a human immunodeficiency virus type 1 integrase inhibitor, following single and repeated administration in healthy adult subjects. Antimicrob. Agents Chemother. 2007, 51, 4284-4289.
141. Zhu, K.; Dobard, C.; Chow, S. A. Requirement for integrase during reverse transcription of human immunodeficiency virus type 1 and the effect of cysteine mutations of integrase on its interactions with reverse transcriptase. J. Virol. 2004, 78, 5045-5055.
142. Englund, G.; Theodore, T. S.; Freed, E. O.; Engleman, A.; Martin, M. A. Integration is required for productive infection of monocyte-derived macrophages by human immunodeficiency virus type 1. J. Virol. 1995, 69, 3216-3219.
143. 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.
144. Quillent, C.; Borman, A. M.; Paulous, S.; Dauguet, C.; Clavel, F. Extensive regions of pol are required for efficient human immunodeficiency virus polyprotein processing and particle maturation. Virology 1996, 219, 29-36.
145. Wu, X.; Liu, H.; Xiao, H.; Conway, J. A.; Hehl, E.; Kalpana, G. V.; Prasad, V.; Kappes, J. C. Human immunodeficiency virus type 1 integrase protein promotes reverse transcription through specific interactions with the nucleoprotein reverse transcription complex. J. Virol. 1999, 73, 2126-2135.
146. Liao, W.-H.; Wang, C.-T. Characterization of human immunodeficiency virus type 1 Pr160 gag-pol mutants with truncations downstream of the protease domain. Virology 2004, 329, 180-188.
147. Nakamura, T.; Masuda, T.; Goto, T.; Sano, K.; Nakai, M.; Harada, S. Lack of infectivity of HIV-1 integrase zinc fingerlike domain mutant with morphologically normal maturation. Biochem. Biophys. Res. Commun. 1997, 239, 715-722.
148. Kalpana, G. V.; Reicin, A.; Cheng, G. S. W.; Sorin, M.; Paik, S.; Goff, S. P. Isolation and characterization of an oligomerization-negative mutant of HIV-1 integrase. Virology 1999, 259, 274-285.
149. Petit, C.; Schwartz, O.; Mammano, F. Oligomerization within virions and subcellular localization of human immunodeficiency virus type 1 integrase. J. Virol. 1999, 73, 5079-5088.
150. Lu, R.; Vandegraaff, N.; Cherepanov, P.; Engelman, A. Lys-34, dispensable for integrase catalysis, is required for preintegration complex function and human immunodeficiency virus type 1 replication. J. Virol. 2005, 79, 12584-12591.
151. Limón, A.; Devroe, E.; Lu, R.; Ghory, H. Z.; Silver, P. A.; Engelman, A. Nuclear localization of human immunodeficiency virus type 1 preintegration complexes (PICs): V165A and R166A are pleiotropic integrase mutants primarily defective for integration, not PIC nuclear import. J. Virol. 2002, 76, 10598-10607.
152. Lu, R.; Ghory, H. Z.; Engelman, A. Genetic analyses of conserved residues in the carboxyl terminal domain of human immunodeficiency virus type 1 integrase. J. Virol. 2005, 79, 10356-10368.
153. Mandal, D.; Feng, Z.; Stoltzfus, C. M. Gag-processing defect of human immunodeficiency virus type 1 integrase E246 and G247 mutants is caused by activation of an overlapping 50 splice site. J. Virol. 2008, 82, 1600-1604.
154. Loeb, D. D.; Swanstrom, R.; Everitt, L.; Manchester, M.; Stamper, S. E.; Hutchison, 3rd, C. A. Complete mutagenesis of the HIV-1 protease. Nature 1989, 340, 397-400.
155. Muller, B.; Restle, T.; Weiss, S.; Gautel, M.; Sczakiel, G.; Goody, R. S. Coexpression of the subunits of the heterodimer of HIV-1 reverse transcriptase in Escherichia coli. J. Biol. Chem. 1989, 264, 13975-13978.
156. Tsurutani, N.; Kubo, M.; Maeda, Y.; Ohashi, T.; Yamamoto, N.; Kannagi, M.; Masuda, T. Identification of critical amino acid residues in human immunodeficiency virus type 1 IN required for efficient proviral DNA formation at steps prior to integration in dividing and nondividing cells. J. Virol. 2000, 74, 4795-4806.
157. Ao, Z.; Fowke, K.; Cohen, E.; Yao, X. Contribution of the C-terminal tri-lysine regions of human immunodeficiency virus type 1 integrase for efficient reverse transcription and viral DNA nuclear import. Retrovirology 2005, 2, 62.
158. Lloyd, A. G.; Ng, Y. S.; Muesing, M. A.; Simon, V.; Mulder, L. C. F. Characterization of HIV-1 integrase Nterminal mutant viruses. Virology 2007, 360, 129-135.
159. Tasara, T.; Maga, G.; Hottiger, M. O.; Hubscher, U. HIV-1 reverse transcriptase and integrase enzymes physically interact and inhibit each other. FEBS Lett. 2001, 507, 39-44.
160. Hehl, E. A.; Joshi, P.; Kalpana, G. V.; Prasad, V. R. Interaction between human immunodeficiency virus type 1 reverse transcriptase and integrase proteins. J. Virol. 2004, 78, 5056-5067.
161. Berthoux, L.; Sebastian, S.; Muesing, M. A.; Luban, J. The role of lysine 186 in HIV-1 integrase multimerization. Virology 2007, 364, 227-236.
162. Padow, M.; Lai, L.; Deivanayagam, C.; DeLucas, L. J.; Weiss, R. B.; Dunn, D. M.;Wu, X.; Kappes, J. C. Replication of chimeric human immunodeficiency virus type 1 (HIV-1) containing HIV-2 integrase (IN): Naturally selected mutations in IN augment DNA synthesis. J. Virol. 2003, 77, 11050-11059.
163. Di Marzio, P.; Choe, S.; Ebright, M.; Knoblauch, R.; Landau, N. R. Mutational analysis of cell cycle arrest, nuclear localization and virion packaging of human immunodeficiency virus type 1 Vpr. J. Virol. 1995, 69, 7909-7916.
164. Lu, Y. L.; Bennett, R. P.;Wills, J.W.; Gorelick, R.; Ratner, L. A leucine triplet repeat sequence (LXX)4 in p6gag is important for Vpr incorporation into human immunodeficiency virus type 1 particles. J. Virol. 1995, 69, 6873-6879.
165. Fletcher, 3rd, T. M.; Soares, M. A.; McPhearson, S.; Hui, H.; Wiskerchen, M.; Muesing,M. A.; Shaw, G.M.; Leavitt, A. D.; Boeke, J. D.; Hahn, B. H. Complementation of integrase function in HIV-1 virions. EMBO J. 1997, 16, 5123-5138.
166. Wu, X.; Liu, H.; Xiao, H.; Conway, J. A.; Hunter, E.; Kappes, J. C. Functional RT and IN incorporated into HIV-1 particles independently of the Gag/Pol precursor protein. EMBO J. 1997, 16, 5113-5122.
167. Bouyac-Bertoia, M.; Dvorin, J. D.; Fouchier, R. A. M.; Jenkins, Y.; Meyer, B. E.; Wu, L. I.; Emerman, M.; Malim, M. H. HIV-1 infection requires a functional integrase NLS. Mol. Cell 2001, 7, 1025-1035.
168. Hamamoto, S.; Nishitsuji, H.; Amagasa, T.; Kannagi, M.; Masuda, T. Identification of a novel human immunodeficiency virus type 1 integrase interactor, Gemin2, that facilitates efficient viral cDNA synthesis in vivo. J. Virol. 2006, 80, 5670-5677.
169. Dobard, C. W.; Briones, M. S.; Chow, S. A. Molecular mechanisms by which human immunodeficiency virus type 1 integrase stimulates the early steps of reverse transcription. J. Virol. 2007, 81, 10037-10046.
170. Weinberg, J. B.; Matthews, T. J.; Cullen, B. R.; Malim, M. H. Productive human immunodeficiency virus type 1 (HIV-1) infection of nonproliferating human monocytes. J. Exp. Med. 1991, 174, 1477-1482.
171. Lewis, P.; Hensel, M.; Emerman, M. Human immunodeficiency virus infection of cells arrested in the cell cycle. EMBO J. 1992, 11, 3053-3058.
172. Roe, T.; Reynolds, T. C.; Yu, G.; Brown, P. O. Integration of murine leukemia virus DNA depends on mitosis. EMBO J, 1993, 12, 2099-2108.
173. Lewis, P. F.; Emerman, M. Passage through mitosis is required for oncoretroviruses but not for the human immunodeficiency virus. J. Virol. 1994, 68, 510-516.
174. Suzuki, Y.; Craigie, R. The road to chromatin-Nuclear entry of retroviruses. Nat. Rev. Microbiol. 2007, 5, 187-196.
175. Kenna, M. A.; Brachmann, C. B.; Devine, S. E.; Boeke, J. D. Invading the yeast nucleus: A nuclear localization signal at the C terminus of Ty1 integrase is required for transposition invivo. Mol. Cell. Biol. 1998, 18, 1115-1124.
176. Moore, S. P.; Rinckel, L. A.; Garfinkel, D. J. ATy1 integrase nuclear localization signal required for retrotransposition. Mol. Cell. Biol. 1998, 18, 1105-1114.
177. Lin, S. S.; Nymark-McMahon, M. H.; Yieh, L.; Sandmeyer, S. B. Integrase mediates nuclear localization of Ty3. Mol. Cell. Biol. 2001, 21, 7826-7838.
178. Pluymers, W.; Cherepanov, P.; Schols, D.; De Clercq, E.; Debyser, Z. Nuclear localization of human immunodeficiency virus type 1 integrase expressed as a fusion protein with green fluorescent protein. Virology 1999, 258, 327-332.
179. Cherepanov, P.; Pluymers, W.; Claeys, A.; Proost, P.; De Clercq, E.; Debyser, Z. High-level expression of active HIV-1 integrase from a synthetic gene in human cells. FASEB J. 2000, 14, 1389-1399.
180. Depienne, C.; Roques, P.; Creminon, C.; Fritsch, L.; Casseron, R.; Dormont, D.; Dargemont, C.; Benichou, S. Cellular distribution and karyophilic properties of matrix, integrase, and Vpr proteins from the human and simian immunodeficiency viruses. Exp. Cell Res. 2000, 260, 387-395.
181. Devroe, E.; Engelman, A.; Silver, P. A. Intracellular transport of human immunodeficiency virus type 1 integrase. J. Cell Sci. 2003, 116, 4401-4408.
182. Jans, D. A.; Hubner, S. Regulation of protein transport to the nucleus: Central role of phosphorylation. Physiol. Rev. 1996, 76, 651-685.
183. Mattaj, I. W.; Ebnglmeier, L. Nucleocytoplasmic transport: The soluble phase. Annu. Rev. Biochem. 1998, 67, 265-306.
184. Kukolj, G.; Jones, K.; Skalka, A. Subcellular localization of avian sarcoma virus and human immunodeficiency virus type 1 integrases. J. Virol. 1997, 71, 843-847.
185. Depienne, C.; Mousnier, A.; Leh, H.; Le Rouzic, E.; Dormont, D.; Benichou, S.; Dargemont, C. Characterization of the nuclear import pathway for HIV-1 integrase. J. Biol. Chem. 2001, 276, 18102-18107.
186. Hearps, A. C.; Jans, D. A. HIV-1 integrase is capable of targeting DNA to the nucleus via an Importin alpha/beta dependent mechanism. Biochem. J. 2006, 398, 475-484.
187. Ochs, R. L.; Muro, Y.; Si, Y.; Ge, H.; Chan, E. K.; Tan, E. M. Autoantibodies to DFS 70 kd/transcription coactivator p75 in atopic dermatitis and other conditions. J. Allergy Clin. Immunol. 2000, 105, 1211-1220.
188. Nishizawa, Y.; Usukura, J.; Singh, D. P.; Chylack, L. T. J.; Shinohara, T. Spatial and temporal dynamics of two alternatively spliced regulatory factors, lens epithelium-derived growth factor (ledgf/p75) and p52, in the nucleus. Cell Tissue Res. 2001, 305, 107-114.
189. Maertens, G.; Cherepanov, P.; Debyser, Z.; Engelborghs, Y.; Engelman, A. Identification and characterization of a functional nuclear localization signal in the HIV-1 integrase interactor LEDGF/p75. J. Biol. Chem. 2004, 279, 33421-33429.
190. Llano, M.; Vanegas, M.; Fregoso, O.; Saenz, D.; Chung, S.; Peretz, M.; Poeschla, E. M. LEDGF/p75 determines cellular trafficking of diverse lentiviral but not murine oncoretroviral integrase proteins and is a component of functional lentiviral preintegration complexes. J. Virol. 2004, 78, 9524-9537.
191. Emiliani, S.; Mousnier, A.; Busschots, K.; Maroun, M.; Van Maele, B.; Tempe, D.; Vandekerckhove, L.; Moisant, F.; Ben-Slama, L.; Witvrouw, M.; Christ, F.; Rain, J. C.; Dargemont, C.; Debyser, Z.; Benarous, R. Integrase mutants defective for interaction with LEDGF/p75 are impaired in chromosome tethering and HIV-1 replication. J. Biol. Chem. 2005, 280, 25517-25523.
192. Mulder, L. C.; Muesing, M. A. Degradation of HIV-1 integrase by the N-end rule pathway. J. Biol. Chem. 2000, 275, 29749-29753.
193. Llano, M.; Delgado, S.; Vanegas, M.; Poeschla, E. M. Lens epithelium-derived growth factor/p75 prevents proteasomal degradation of HIV-1 integrase. J. Biol. Chem. 2004, 279, 55570-55577.
194. Gallay, P.; Hope, T.; Chin, D.; Trono, D. HIV-1 infection of nondividing cells through the recognition of integrase by the importin/karyopherin pathway. Proc. Natl. Acad. Sci. USA 1997, 94, 9825-9830.
195. Petit, C.; Schwartz, O.; Mammano, F. The karyophilic properties of human immunodeficiency virus type 1 integrase are not required for nuclear import of proviral DNA. J. Virol. 2000, 74, 7119-7126.
196. Dvorin, J. D.; Bell, P.; Maul, G. G.; Yamashita, M.; Emerman, M.; Malim, M. H. Reassessment of the roles of integrase and the central DNA flap in human immunodeficiency virus type 1 nuclear import. J. Virol. 2002, 76, 12087-12096.
197. Ikeda, T.; Nishitsuji, H.; Zhou, X.; Nara, N.; Ohashi, T.; Kannagi, M.; Masuda, T. Evaluation of the functional involvement of human immunodeficiency virus type 1 integrase in nuclear import of viral cDNA during acute infection. J. Virol. 2004, 78, 11563-11573.
198. Fassati, A.; Gorlich, D.; Harrison, I.; Zaytseva, L.; Mingot, J. M. Nuclear import of HIV-1 intracellular reverse transcription complexes is mediated by importin 7. EMBO J. 2003, 22, 3675-3685.
199. Ao, Z.; Huang, G.; Yao, H.; Xu, Z.; Labine, M.; Cochrane, A. W.; Yao, X. Interaction of human immunodeficiency virus type 1 integrase with cellular nuclear import receptor importin 7 and its impact on viral replication. J. Biol. Chem. 2007, 282, 13456-13467.
200. Zielske, S. P.; Stevenson, M. Importin 7 may be dispensable for human immunodeficiency virus type 1 and simian immunodeficiency virus infection of primary macrophages. J. Virol. 2005, 79, 11541-11546.
201. Butler, S. L.; Johnson, E. P.; Bushman, F. D. Human immunodeficiency virus cDNA metabolism: Notable stability of two-long terminal repeat circles. J. Virol. 2002, 76, 3739-3747.
202. Zheng, Y.; Ourmanov, I.; Hirsch, V. M. Persistent transcription of a nonintegrating mutant of simian immunodeficiency virus in rhesus macrophages. Virology 2008, 372, 291-299.
203. Gerrard, J. A.; Hutton, C. A.; Perugini, M. A. Inhibiting protein-protein interactions as an emerging paradigm for drug discovery. Mini Rev. Med. Chem. 2007, 7, 151-157.
204. Rice, A. P.; Sutton, R. E. Targeting protein-protein interactions for HIV therapeutics. Future HIV Ther. 2007, 1, 369-385.