Dynamic Oligomerization of Integrase Orchestrates HIV Nuclear Entry

Scientific Reports

Volumn 6, Issue , 2016, Pages

  Borrenberghs, Doortje ^a,b   Dirix, Lieve ^a,b   De Wit, Flore ^a   Rocha, Susana ^b   Blokken, Jolien ^a   De Houwer, Stéphanie ^a   Gijsbers, Rik ^a   Christ, Frauke ^a   Hofkens, Johan ^b   Hendrix, Jelle ^b,c   Debyser, Zeger ^a  

^a DEPARTMENT OF PHARMACEUTICAL AND PHARMACOLOGICAL SCIENCES   (Belgium)

^b Katholieke Universiteit Leuven   (Belgium)

^c HASSELT UNIVERSITY   (Belgium)

Author keywords

[No Author keywords available]

Indexed keywords

INTEGRASE; LENS EPITHELIUM-DERIVED GROWTH FACTOR; P31 INTEGRASE PROTEIN, HUMAN IMMUNODEFICIENCY VIRUS 1; SIGNAL PEPTIDE;

CELL LINE; CELL NUCLEUS; CHEMISTRY; CHROMATIN; CONFOCAL MICROSCOPY; ENZYMOLOGY; FLUORESCENCE RESONANCE ENERGY TRANSFER; GENETICS; HELA CELL LINE; HUMAN; HUMAN IMMUNODEFICIENCY VIRUS 1; METABOLISM; NUCLEAR PORE; NUCLEOCYTOPLASMIC TRANSPORT; PHYSIOLOGY; PROTEIN MULTIMERIZATION;

ACTIVE TRANSPORT, CELL NUCLEUS; CELL LINE; CELL NUCLEUS; CHROMATIN; FLUORESCENCE RESONANCE ENERGY TRANSFER; HELA CELLS; HIV INTEGRASE; HIV-1; HUMANS; INTERCELLULAR SIGNALING PEPTIDES AND PROTEINS; MICROSCOPY, CONFOCAL; NUCLEAR PORE; PROTEIN MULTIMERIZATION;

EID: 84994888570     PISSN: None     EISSN: 20452322     Source Type: Journal    
DOI: 10.1038/srep36485     Document Type: Article

References (86)

1. De Rijck, J., Vandekerckhove, L., Christ, F. & Debyser, Z. Lentiviral nuclear import: a complex interplay between virus and host. Bioessays 29, 441-451 (2007).
2. Suzuki, Y. & Craigie, R. The road to chromatin-nuclear entry of retroviruses. Nat Rev Microbiol 5, 187-196 (2007).
3. Arhel, N. Revisiting HIV-1 uncoating. Retrovirology 7 (2010).
4. Hilditch, L. & Towers, G. J. A model for cofactor use during HIV-1 reverse transcription and nuclear entry. Current Opinion in Virology 4, 32-36 (2014).
5. Flatt, J. W. & Greber, U. F. Misdelivery at the Nuclear Pore Complex-Stopping a Virus Dead in Its Tracks. Cells 4, 277-296 (2015).
6. Peng, K. et al. Quantitative microscopy of functional HIV post-entry complexes reveals association of replication with the viral capsid. Elife 3, e04114 (2014).
7. Hulme, A. E., Kelley, Z., Foley, D. & Hope, T. J. Complementary Assays Reveal a Low Level of CA Associated with Viral Complexes in the Nuclei of HIV-1-Infected Cells. J Virol 89, 5350-5361 (2015).
8. Campbell, E. M. & Hope, T. J. HIV-1 capsid: the multifaceted key player in HIV-1 infection. Nat Rev Microbiol 13, 471-483 (2015).
9. Chin, Christopher R. et al. Direct Visualization of HIV-1 Replication Intermediates Shows that Capsid and CPSF6 Modulate HIV-1 Intra-nuclear Invasion and Integration. Cell Reports 13, 1717-1731 (2015).
10. Di Nunzio, F. et al. Human nucleoporins promote HIV-1 docking at the nuclear pore, nuclear import and integration. PLoS One 7, e46037 (2012).
11. Konig, R. et al. Global analysis of host-pathogen interactions that regulate early-stage HIV-1 replication. Cell 135, 49-60 (2008).
12. Brass, A. L. et al. Identification of host proteins required for HIV infection through a functional genomic screen. Science 319, 921-926 (2008).
13. Zhang, R., Mehla, R. & Chauhan, A. Perturbation of host nuclear membrane component RanBP2 impairs the nuclear import of human immunodeficiency virus -1 preintegration complex (DNA). PLoS One 5, e15620 (2010).
14. Schaller, T. et al. HIV-1 capsid-cyclophilin interactions determine nuclear import pathway, integration targeting and replication efficiency. PLoS Pathog 7, e1002439 (2011).
15. Matreyek, K. A. & Engelman, A. The requirement for nucleoporin NUP153 during human immunodeficiency virus type 1 infection is determined by the viral capsid. J Virol 85, 7818-7827 (2011).
16. Woodward, C. L., Prakobwanakit, S., Mosessian, S. & Chow, S. A. Integrase interacts with nucleoporin NUP153 to mediate the nuclear import of human immunodeficiency virus type 1. J Virol 83, 6522-6533 (2009).
17. Taltynov, O., Desimmie, B. A., Demeulemeester, J., Christ, F. & Debyser, Z. Cellular cofactors of lentiviral integrase: from target validation to drug discovery. Molecular Biology International 2012, 863405 (2012).
18. 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 22, 3675-3685 (2003).
19. Ao, Z. et al. Importin alpha3 interacts with HIV-1 integrase and contributes to HIV-1 nuclear import and replication. J Virol 84, 8650-8663 (2010).
20. Christ, F. et al. Transportin-SR2 imports HIV into the nucleus. Curr Biol 18, 1192-1202 (2008).
21. Sirven, A. et al. The human immunodeficiency virus type-1 central DNA flap is a crucial determinant for lentiviral vector nuclear import and gene transduction of human hematopoietic stem cells. Blood 96, 4103-4110 (2000).
22. De Rijck, J. & Debyser, Z. The central DNA flap of the human immunodeficiency virus type 1 is important for viral replication. Biochem Biophys Res Commun 349, 1100-1110 (2006).
23. Craigie, R. HIV integrase, a brief overview from chemistry to therapeutics. J Biol Chem 276, 23213-23216 (2001).
24. Faure, A. et al. HIV-1 integrase crosslinked oligomers are active in vitro. Nucleic Acids Research 33, 977-986 (2005).
25. Guiot, E. et al. Relationship between the oligomeric status of HIV-1 integrase on DNA and enzymatic activity. The Journal of Biological Chemistry 281, 22707-22719 (2006).
26. Li, M., Mizuuchi, M., Burke, T. R. Jr. & Craigie, R. Retroviral DNA integration: reaction pathway and critical intermediates. EMBO Journal 25, 1295-1304 (2006).
27. 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 Journal 12, 3269-3275 (1993).
28. Delelis, O., Carayon, K., Saib, A., Deprez, E. & Mouscadet, J. F. Integrase and integration: biochemical activities of HIV-1 integrase. Retrovirology 5, 114 (2008).
29. Hare, S., Gupta, S. S., Valkov, E., Engelman, A. & Cherepanov, P. Retroviral intasome assembly and inhibition of DNA strand transfer. Nature 464, 232-236 (2010).
30. Wu, X., Li, Y., Crise, B. & Burgess, S. M. Transcription start regions in the human genome are favored targets for MLV integration. Science 300, 1749-1751 (2003).
31. Mitchell, R. S. et al. Retroviral DNA integration: ASLV, HIV, and MLV show distinct target site preferences. PLoS Biol 2, E234 (2004).
32. Cherepanov, P. et al. HIV-1 integrase forms stable tetramers and associates with LEDGF/p75 protein in human cells. Journal of Biological Chemistry 278, 372-381 (2003).
33. Ciuffi, A. et al. A role for LEDGF/p75 in targeting HIV DNA integration. Nature Medicine 11, 1287-1289 (2005).
34. Hendrix, J. et al. The transcriptional co-activator LEDGF/p75 displays a dynamic scan-and-lock mechanism for chromatin tethering. Nucleic Acids Research 39, 1310-1325 (2011).
35. Turlure, F., Maertens, G., Rahman, S., Cherepanov, P. & Engelman, A. A tripartite DNA-binding element, comprised of the nuclear localization signal and two AT-hook motifs, mediates the association of LEDGF/p75 with chromatin in vivo. Nucleic Acids Res. 34, 1663-1675 (2006).
36. Llano, M. et al. An essential role for LEDGF/p75 in HIV integration. Science 314, 461-464 (2006).
37. Debyser, Z., Christ, F., De Rijck, J. & Gijsbers, R. Host factors for retroviral integration site selection. Trends Biochem Sci 40, 108-116 (2015).
38. Emiliani, S. et al. Integrase Mutants Defective for Interaction with LEDGF/p75 Are Impaired in Chromosome Tethering and HIV-1 Replication. Journal of Biological Chemistry 280, 25517-25523 (2005).
39. Hombrouck, A. et al. Virus evolution reveals an exclusive role for LEDGF/p75 in chromosomal tethering of HIV. PLoS Pathog. 3 (2007).
40. Vandekerckhove, L. et al. Transient and stable knockdown of the integrase cofactor LEDGF/p75 reveals its role in the replication cycle of human immunodeficiency virus. Journal of Virology 80, 1886-1896 (2006).
41. Shun, M.-C. et al. LEDGF/p75 functions downstream from preintegration complex formation to effect gene-specific HIV-1 integration. Genes & Development 21, 1767-1778 (2007).
42. Schrijvers, R. et al. LEDGF/p75-Independent HIV-1 Replication Demonstrates a Role for HRP-2 and Remains Sensitive to Inhibition by LEDGINs. PLoS Pathog. 8, e1002558 (2012).
43. Busschots, K. et al. Identification of the LEDGF/p75 binding site in HIV-1 integrase. Journal of Molecular Biology 365, 1480-1492 (2007).
44. Christ, F. et al. Rational design of small-molecule inhibitors of the LEDGF/p75-integrase interaction and HIV replication. Nature Chemical Biology 6, 442-448 (2010).
45. Christ, F. et al. Small-molecule inhibitors of the LEDGF/p75 binding site of integrase block HIV replication and modulate integrase multimerization. Antimicrob Agents Chemother 56, 4365-4374 (2012).
46. Kessl, J. J. et al. Multimode, cooperative mechanism of action of allosteric HIV-1 integrase inhibitors. J Biol Chem 287, 16801-16811 (2012).
47. Tsiang, M. et al. New class of HIV-1 integrase (IN) inhibitors with a dual mode of action. The Journal of Biological Chemistry 287, 21189-21203 (2012).
48. Gupta, K. et al. Allosteric inhibition of human immunodeficiency virus integrase: late block during viral replication and abnormal multimerization involving specific protein domains. J Biol Chem 289, 20477-20488 (2014).
49. Desimmie, B. A. et al. LEDGINs inhibit late stage HIV-1 replication by modulating integrase multimerization in the virions. Retrovirology 10, 57 (2013).
50. Le Rouzic, E. et al. Dual inhibition of HIV-1 replication by integrase-LEDGF allosteric inhibitors is predominant at the postintegration stage. Retrovirology 10, 144 (2013).
51. Jurado, K. A. & Engelman, A. Multimodal mechanism of action of allosteric HIV-1 integrase inhibitors. Expert Rev Mol Med 15, e14 (2013).
52. Balakrishnan, M. et al. Non-Catalytic Site HIV-1 Integrase Inhibitors Disrupt Core Maturation and Induce a Reverse Transcription Block in Target Cells. PLoS One 8, 10.1371/journal.pone.0074163 (2013).
53. Borrenberghs, D. et al. HIV virions as nanoscopic test tubes for probing oligomerization of the integrase enzyme. ACS Nano 8, 3531-3545 (2014).
54. Albanese, A., Arosio, D., Terreni, M. & Cereseto, A. HIV-1 Pre-Integration Complexes Selectively Target Decondensed Chromatin in the Nuclear Periphery. Plos One 3, 2413 (2008).
55. Francis, A. C. et al. Second generation imaging of nuclear/cytoplasmic HIV-1 complexes. AIDS Res Hum Retroviruses 30, 717-726 (2014).
56. Blair, W. S. et al. HIV capsid is a tractable target for small molecule therapeutic intervention. PLoS Pathog 6, e1001220 (2010).
57. Shi, J., Zhou, J., Shah, V. B., Aiken, C. & Whitby, K. Small-molecule inhibition of human immunodeficiency virus type 1 infection by virus capsid destabilization. J Virol 85, 542-549 (2011).
58. Hazuda, D. J. et al. Inhibitors of strand transfer that prevent integration and inhibit HIV-1 replication in cells. Science 287, 646-650 (2000).
59. Sato, M. et al. Novel HIV-1 integrase inhibitors derived from quinolone antibiotics. J Med Chem 49, 1506-1508 (2006).
60. Butler, S. L., Hansen, M. S. & Bushman, F. D. A quantitative assay for HIV DNA integration in vivo. Nat Med 7, 631-634 (2001).
61. Salahuddin, S. Z. et al. Restricted expression of human T-cell leukemia-lymphoma virus (HTLV) in transformed human umbilical cord blood lymphocytes. Virology 129, 51-64 (1983).
62. Maertens, G. N., Cherepanov, P. & Engelman, A. Transcriptional co-activator p75 binds and tethers the Myc-interacting protein JPO2 to chromatin. J. Cell Sci. 119, 2563-2571 (2006).
63. McKee, C. J. et al. Dynamic modulation of HIV-1 integrase structure and function by cellular lens epithelium-derived growth factor (LEDGF) protein. The Journal of Biological Chemistry 283, 31802-31812 (2008).
64. Cherepanov, P., Ambrosio, A. L., Rahman, S., Ellenberger, T. & Engelman, A. Structural basis for the recognition between HIV-1 integrase and transcriptional coactivator p75. Proc. Natl. Acad. Sci. USA (2005).
65. Tsutsui, K. M., Sano, K., Hosoya, O., Miyamoto, T. & Tsutsui, K. Nuclear protein LEDGF/p75 recognizes supercoiled DNA by a novel DNA-binding domain. Nucleic Acids Research (2011).
66. Gijsbers, R. et al. Role of the PWWP domain of lens epithelium-derived growth factor (LEDGF)/p75 cofactor in lentiviral integration targeting. J Biol Chem 286, 41812-41825 (2011).
67. McNeely, M. et al. In vitro DNA tethering of HIV-1 integrase by the transcriptional coactivator LEDGF/p75. J Mol Biol 410, 811-830 (2011).
68. De Rijck, J. et al. Overexpression of the lens epithelium-derived growth factor/p75 integrase binding domain inhibits human immunodeficiency virus replication. J. Virol. 80, 11498-11509 (2006).
69. Rasaiyaah, J. et al. HIV-1 evades innate immune recognition through specific cofactor recruitment. Nature 503, 402-405 (2013).
70. Campbell, E. M., Perez, O., Melar, M. & Hope, T. J. Labeling HIV-1 virions with two fluorescent proteins allows identification of virions that have productively entered the target cell. Virology 360, 286-293 (2007).
71. Espeseth, A. S. et al. HIV-1 integrase inhibitors that compete with the target DNA substrate define a unique strand transfer conformation for integrase. Proc Natl Acad Sci USA 97, 11244-11249 (2000).
72. De Houwer, S. et al. The HIV-1 integrase mutant R263A/K264A is 2-fold defective for TRN-SR2 binding and viral nuclear import. J Biol Chem 289, 25351-25361 (2014).
73. Cribier, A. et al. Mutations affecting interaction of integrase with TNPO3 do not prevent HIV-1 cDNA nuclear import. Retrovirology 8, 104 (2011).
74. Arhel, N. J. et al. HIV-1 DNA Flap formation promotes uncoating of the pre-integration complex at the nuclear pore. Embo J 26, 3025-3037 (2007).
75. Lelek, M. et al. Superresolution imaging of HIV in infected cells with FlAsH-PALM. Proceedings of the National Academy of Sciences 109, 8564-8569 (2012).
76. Pante, N. & Kann, M. Nuclear pore complex is able to transport macromolecules with diameters of about 39 nm. Mol Biol Cell 13, 425-434 (2002).
77. Whittaker, G. R. Virus nuclear import. Adv Drug Deliv Rev 55, 733-747 (2003).
78. Crowther, R. A. et al. Three-dimensional structure of hepatitis B virus core particles determined by electron cryomicroscopy. Cell 77, 943-950 (1994).
79. Wildy, P., Russell, W. C. & Horne, R. W. The morphology of herpes virus. Virology 12, 204-222 (1960).
80. Briggs, J. A., Wilk, T., Welker, R., Krausslich, H. G. & Fuller, S. D. Structural organization of authentic, mature HIV-1 virions and cores. EMBO Journal 22, 1707-1715 (2003).
81. Desimmie, B. A. et al. HIV-1 IN/Pol recruits LEDGF/p75 into viral particles. Retrovirology 12, 16 (2015).
82. Feng, L., Larue, R., Slaughter, A., Kessl, J. & Kvaratskhelia, M. In The Future of HIV-1 Therapeutics, Vol. 389. (eds Torbett, B. E., Goodsell, D. S. & Richman, D. D.) 93-119 (Springer International Publishing, 2015).
83. Raghavendra, N. K. & Engelman, A. LEDGF/p75 interferes with the formation of synaptic nucleoprotein complexes that catalyze full-site HIV-1 DNA integration in vitro: implications for the mechanism of viral cDNA integration. Virology 360, 1-5 (2007).
84. Zack, G. W., Rogers, W. E. & Latt, S. A. Automatic measurement of sister chromatid exchange frequency. J Histochem Cytochem 25, 741-753 (1977).
85. Dedecker, P., Duwe, S., Neely, R. K. & Zhang, J. Localizer: fast, accurate, open-source, and modular software package for superresolution microscopy. Journal of Biomedical Optics 17, 126008 (2012).
86. Bastiaens, P. I., Majoul, I. V., Verveer, P. J., Soling, H. D. & Jovin, T. M. Imaging the intracellular trafficking and state of the AB5 quaternary structure of cholera toxin. Embo Journal 15, 4246-4253 (1996).