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Molecular Medicine

, Volume 10, Issue 1–6, pp 1–5 | Cite as

A Hard Way to the Nucleus

  • Michael Bukrinsky
In Overview

Abstract

As a member of the Retrovirus family, human immunodeficiency virus (HIV), a causative agent of AIDS, replicates by integrating its genome into the host cell’s nuclear DNA. However, in contrast to most retroviruses that depend on mitotic dissolution of the nuclear envelope to gain access to the host cell’s genome, the HIV pre-integration complex can enter the nucleus of the target cell during the interphase. Such capacity greatly enhances HIV replication and allows the virus to productively infect terminally differentiated nonproliferating cells, such as macrophages. Infection of macrophages is a critical factor in the pathogenesis of diseases caused by HIV-1 and other lentiviruses. The mechanisms responsible for this unusual feature of HIV have enticed researchers since the early 90s, when the first characterization of the HIV-1 pre-integration complex was reported. Several viral factors, including matrix protein, integrase, viral protein R, and central DNA flap, have been proposed as regulators of HIV-1 nuclear import, only to be later shown as nonessential for this process. As a result, after more than a decade of intense research, there is still no consensus on which HIV-1 and cellular proteins control this critical step in HIV-1 replication. In this review, we will discuss recent advances and suggest possible solutions to the controversial issue of HIV-1 nuclear import.

References

  1. 1.
    Bukrinsky MI, Haggerty S, Dempsey MP, Sharova N, Adzhubel A, Spitz L, Lewis P, Goldfarb D, Emerman M, and Stevenson M. (1993) A nuclear localization signal within HIV-1 matrix protein that governs infection of non-dividing cells. Nature 365:666–9.CrossRefGoogle Scholar
  2. 2.
    Lewis PF, Emerman M. (1994) Passage through mitosis is required for oncoretro-viruses but not for the human immunodeficiency virus. J. Virol. 68:510–6.PubMedPubMedCentralGoogle Scholar
  3. 3.
    Weinberg JB, Matthews TJ, Cullen BR, Malim MH. (1991) Productive human immunodeficiency virus type 1 (HIV-1) infection of nonproliferating human monocytes. J. Exp. Med. 174:1477–82.CrossRefGoogle Scholar
  4. 4.
    Bukrinsky MI, Sharova N, Dempsey MP, Stanwick TL, Bukrinskaya AG, Haggerty S, Stevenson M. (1992) Active nuclear import of human immunodeficiency virus type 1 preintegration complexes. Proc. Natl. Acad. Sci. U.S.A. 89:6580–4.CrossRefGoogle Scholar
  5. 5.
    Lewis P, Hensel M, Emerman M. (1992) Human immunodeficiency virus infection of cells arrested in the cell cycle. EMBO J. 11:3053–8.CrossRefGoogle Scholar
  6. 6.
    Li G, Simm M, Potash MJ, Volsky DJ. (1993) Human immunodeficiency virus type 1 DNA synthesis, integration, and efficient viral replication in growth-arrested T cells. J. Virol. 67:3969–77.PubMedPubMedCentralGoogle Scholar
  7. 7.
    Gallay P, Swingler S, Aiken C, Trono D. (1995) HIV-1 infection of nondividing cells: C-terminal tyrosine phosphorylation of the viral matrix protein is a key regulator. Cell 80:379–88.CrossRefGoogle Scholar
  8. 8.
    Roe T, Reynolds TC, Yu G, Brown PO. (1993) Integration of murine leukemia virus DNA depends on mitosis. EMBO J. 12:2099–108.CrossRefGoogle Scholar
  9. 9.
    Briggs JA, Wilk T, Welker R, Krausslich HG, Fuller SD. 2003. Structural organization of authentic, mature HIV-1 virions and cores. EMBO J. 22:1707–15.CrossRefGoogle Scholar
  10. 10.
    Bukrinsky MI, Sharova N, McDonald TL, Pushkarskaya T, Tarpley WG, Stevenson M. (1993) Association of integrase, matrix, and reverse transcriptase antigens of human immunodeficiency virus type 1 with viral nucleic acids following acute infection. Proc. Natl. Acad. Sci. U.S.A. 90:6125–9.CrossRefGoogle Scholar
  11. 11.
    Fassati A, Goff SP. (2001) Characterization of intracellular reverse transcription complexes of human immunodeficiency virus type 1. J. Virol. 75:3626–35.CrossRefGoogle Scholar
  12. 12.
    Bowerman B, Brown PO, Bishop JM, Varmus HE. (1989) A nucleoprotein complex mediates the integration of retroviral DNA. Genes Dev. 3:469–78.CrossRefGoogle Scholar
  13. 13.
    Miller MD, Farnet CM, Bushman FD. 1997. Human immunodeficiency virus type 1 preintegration complexes: studies of organization and composition. J. Virol. 71:5382–90.PubMedPubMedCentralGoogle Scholar
  14. 14.
    Bukrinskaya A, Brichacek B, Mann A, Stevenson M. (1998) Establishment of a functional human immunodeficiency virus type 1 (HIV-1) reverse transcription complex involves the cytoskeleton. J. Exp. Med. 188:2113–25.CrossRefGoogle Scholar
  15. 15.
    McDonald D, Vodicka MA, Lucero G, Svitkina TM, Borisy GG, Emerman M, Hope TJ. (2002) Visualization of the intracellular behavior of HIV in living cells. J. Cell Biol. 159:441–52.CrossRefGoogle Scholar
  16. 16.
    Taunton J. (2001) Actin filament nucleation by endosomes, lysosomes and secretory vesicles. Curr. Opin. Cell Biol. 13:85–91.CrossRefGoogle Scholar
  17. 17.
    Sodeik B, Ebersold MW, Helenius A. (1997) Microtubule-mediated transport of incoming herpes simplex virus 1 capsids to the nucleus. J. Cell Biol. 136:1007–21.CrossRefGoogle Scholar
  18. 18.
    Suomalainen M, Nakano MY, Keller S, Boucke K, Stidwill RP, Greber UF. (1999) Microtubule-dependent plus- and minus end-directed motilities are competing processes for nuclear targeting of adenovirus. J. Cell Biol. 144:657–72.CrossRefGoogle Scholar
  19. 19.
    de Noronha CM, Sherman MP, Lin HW, Cavrois MV, Moir RD, Goldman RD, Greene WC. (2001) Dynamic disruptions in nuclear envelope architecture and integrity induced by HIV-1 Vpr. Science 294:1105–8.CrossRefGoogle Scholar
  20. 20.
    Gupta K, Ott D, Hope TJ, Siliciano RF, Boeke JD. (2000) A human nuclear shuttling protein that interacts with human immunodeficiency virus type 1 matrix is packaged into virions. J. Virol. 74:11811–24.CrossRefGoogle Scholar
  21. 21.
    Zennou V, Petit C, Guetard D, Nerhbass U, Montagnier L, Charneau P. (2000) HIV-1 genome nuclear import is mediated by a central DNA flap. Cell 101: 173–85.CrossRefGoogle Scholar
  22. 22.
    Sirven A, Pflumio F, Zennou V, Titeux M, Vainchenker W, Coulombel L, Dubart-Kupperschmitt A, Charneau P. (2000) 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 96:4103–10.PubMedGoogle Scholar
  23. 23.
    Van Maele B, De Rijck J, De Clercq E, Debyser Z. (2003) Impact of the central polypurine tract on the kinetics of human immunodeficiency virus type 1 vector transduction. J. Virol. 77:4685–94.CrossRefGoogle Scholar
  24. 24.
    Dvorin JD, Bell P, Maul GG, Yamashita M, Emerman M, Malim MH. (2002) Reassessment of the roles of integrase and the central DNA flap in human immunodeficiency virus type 1 nuclear import. J. Virol. 76:12087–96.CrossRefGoogle Scholar
  25. 25.
    Limon A, Nakajima N, Lu R, Ghory HZ, Engelman A. (2002) Wild-type levels of nuclear localization and human immunodeficiency virus type 1 replication in the absence of the central DNA flap. J. Virol. 76:12078–86.CrossRefGoogle Scholar
  26. 26.
    von Schwedler U, Kornbluth RS, Trono D. (1994) The nuclear localization signal of the matrix protein of human immunodeficiency virus type 1 allows the establishment of infection in macrophages and quiescent T lymphocytes. Proc. Natl. Acad. Sci. U.S.A. 91:6992–6.CrossRefGoogle Scholar
  27. 27.
    Nadler SG, Tritschler D, Haffar OK, Blake J, Bruce AG, Cleaveland JS. (1997) Differential expression and sequence-specific interaction of karyopherin alpha with nuclear localization sequences. J. Biol. Chem. 272:4310–5.CrossRefGoogle Scholar
  28. 28.
    Dingwall C, Laskey RA. 1991. Nuclear targeting sequences—a consensus? Trends Biochem. Sci. 16:478–81.CrossRefGoogle Scholar
  29. 29.
    Haffar OK, Popov S, Dubrovsky L, Agostini I, Tang H, Pushkarsky T, Nadler SG, Bukrinsky M. (2000) Two nuclear localization signals in the HIV-1 matrix protein regulate nuclear import of the HIV-1 pre-integration complex. J. Mol. Biol. 299:359–68.CrossRefGoogle Scholar
  30. 30.
    Mattaj IW, Englmeier L. (1998) Nucleocytoplasmic transport: the soluble phase. Annu. Rev. Biochem. 67:265–306.CrossRefGoogle Scholar
  31. 31.
    Rexach M, Blobel G. (1995) Protein import into nuclei: association and dissociation reactions involving transport substrate, transport factors, and nucleoporins. Cell 83:683–92.CrossRefGoogle Scholar
  32. 32.
    Gallay P, Stitt V, Mundy C, Oettinger M, Trono D. (1996) Role of the karyopherin pathway in human immunodeficiency virus type 1 nuclear import. J. Virol. 70:1027–32.PubMedPubMedCentralGoogle Scholar
  33. 33.
    Fouchier RA, Meyer BE, Simon JH, Fischer U, Malim MH. (1997) HIV-1 infection of non-dividing cells: evidence that the amino-terminal basic region of the viral matrix protein is important for Gag processing but not for post-entry nuclear import. EMBO J. 16:4531–9.CrossRefGoogle Scholar
  34. 34.
    Freed EO, Englund G, Martin MA. (1995) Role of the basic domain of human immunodeficiency virus type 1 matrix in macrophage infection. J. Virol. 69:3949–54.PubMedPubMedCentralGoogle Scholar
  35. 35.
    Reil H, Bukovsky AA, Gelderblom HR, Gottlinger HG. 1998. Efficient HIV-1 replication can occur in the absence of the viral matrix protein. EMBO J. 17:2699–708.CrossRefGoogle Scholar
  36. 36.
    Gallay P, Hope T, Chin D, Trono D. (1997) HIV-1 infection of nondividing cells through the recognition of integrase by the importin/karyopherin pathway. Proc. Natl. Acad. Sci. U.S.A. 94:9825–30.CrossRefGoogle Scholar
  37. 37.
    Bouyac-Bertoia M, Dvorin JD, Fouchier RA, Jenkins Y, Meyer BE, Wu LI, Emerman M, Malim MH. 2001. HIV-1 infection requires a functional integrase nls. Mol. Cell 7:1025–35.CrossRefGoogle Scholar
  38. 38.
    Limon A, Devroe E, Lu R, Ghory HZ, Silver PA, Engelman A. 2002. 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. 76:10598–607.CrossRefGoogle Scholar
  39. 39.
    Fassati A, Gorlich D, Harrison I, Zaytseva L, Mingot JM. (2003) Nuclear import of HIV-1 intracellular reverse transcription complexes is mediated by importin 7. EMBO J. 22:3675–85.CrossRefGoogle Scholar
  40. 40.
    Jakel S, Gorlich D. 1998. Importin beta, transportin, RanBP5, and RanBP7 mediate nuclear import of ribosomal proteins in mammalian cells. EMBO J. 17:4491–502.CrossRefGoogle Scholar
  41. 41.
    Heinzinger NK et al. (1994) The Vpr protein of human immunodeficiency virus type 1 influences nuclear localization of viral nucleic acids in nondividing host cells. Proc. Natl. Acad. Sci. U.S.A. 91:7311–5.CrossRefGoogle Scholar
  42. 42.
    Emerman M, Bukrinsky M, Stevenson M. (1994) HIV-1 infection of non-dividing cells. Nature 369:107–8.CrossRefGoogle Scholar
  43. 43.
    Dahl K, Martin K, Miller G. (1987) Differences among human immunodeficiency virus strains in their capacities to induce cytolysis or persistent infection of a lymphoblastoid cell line immortalized by Epstein-Barr virus. J. Virol. 61:1602–8.PubMedPubMedCentralGoogle Scholar
  44. 44.
    Stewart SA, Poon B, Jowett JB, Chen IS. (1997) Human immunodeficiency virus type 1 Vpr induces apoptosis following cell cycle arrest. J. Virol. 71:5579–92.PubMedPubMedCentralGoogle Scholar
  45. 45.
    Connor RI, Chen BK, Choe S, Landau NR. (1995) Vpr is required for efficient replication of human immunodeficiency virus type-1 in mononuclear phagocytes. Virology 206:935–44.CrossRefGoogle Scholar
  46. 46.
    Nie Z, Bergeron D, Subbramanian RA, Yao XJ, Checroune F, Rougeau N, Cohen EA. (1998) The putative alpha helix 2 of human immunodeficiency virus type 1 Vpr contains a determinant which is responsible for the nuclear translocation of proviral DNA in growth-arrested cells. J. Virol. 72:4104–15.PubMedPubMedCentralGoogle Scholar
  47. 47.
    Jenkins Y, McEntee M, Weis K, Greene WC. (1998) Characterization of HIV-1 Vpr nuclear import: analysis of signals and pathways. J. Cell Biol. 143:875–85.CrossRefGoogle Scholar
  48. 48.
    Popov S, Rexach M, Ratner L, Blobel G, Bukrinsky M. (1998) Viral protein R regulates docking of the HIV-1 preintegration complex to the nuclear pore complex. J. Biol. Chem. 273:13347–52.CrossRefGoogle Scholar
  49. 49.
    Popov S, Rexach M, Zybarth G, Reiling N, Lee MA, Ratner L, Lane CM, Moore MS, Blobel G, Bukrinsky M. (1998) Viral protein R regulates nuclear import of the HIV-1 pre-integration complex. EMBO J. 17:909–17.CrossRefGoogle Scholar
  50. 50.
    Vodicka MA, Koepp DM, Silver PA, Emerman M. (1998) HIV-1 Vpr interacts with the nuclear transport pathway to promote macrophage infection. Genes Dev. 12:175–85.CrossRefGoogle Scholar
  51. 51.
    Fouchier RA et al. (1998) Interaction of the human immunodeficiency virus type 1 Vpr protein with the nuclear pore complex. J. Virol. 72:6004–13.PubMedPubMedCentralGoogle Scholar
  52. 52.
    Le Rouzic E et al. (2002) Docking of HIV-1 Vpr to the nuclear envelope is mediated by the interaction with the nucleoporin hCG1. J. Biol. Chem. 277:45091–8.CrossRefGoogle Scholar
  53. 53.
    Weiss RA. (2003) HIV and AIDS: looking ahead. Nat. Med. 9:887–91.CrossRefGoogle Scholar
  54. 54.
    Turelli P et al. (2001) Cytoplasmic recruitment of INI1 and PML on incoming HIV preintegration complexes: interference with early steps of viral replication. Mol. Cell 7:1245–54.CrossRefGoogle Scholar
  55. 55.
    Nermut MV, Fassati A. (2003) Structural analyses of purified human immunodeficiency virus type 1 intracellular reverse transcription complexes. J. Virol. 77:8196–206.CrossRefGoogle Scholar

Copyright information

© Feinstein Institute for Medical Research 2004

Authors and Affiliations

  1. 1.George Washington University Medical CenterWashington, DCUSA

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