HIV infection of non-dividing cells: a divisive problem

Sorin M, Kalpana GV: Dynamics of virus-host interplay in HIV-1 replication. Curr HIV Res. 2006, 4: 117-30. 10.2174/157016206776055048. Yamashita M, Emerman M: Retroviral infection of non-dividing cells: old and new perspectives. Virology. 2006, 344: 88-93. 10.1016/j.virol.2005.09.012. Campbell EM, Hope TJ: Gene therapy progress and prospects: viral trafficking during infection. Gene Ther. 2005, 12: 1353-9. 10.1038/sj.gt.3302585. Lehmann-Che J, Saib A: Early stages of HIV replication: how to hijack cellular functions for a successful infection. AIDS Rev. 2004, 6: 199-207. Bukrinsky M: A hard way to the nucleus. Mol Med. 2004, 10: 1-5. Lim RY, Aebi U, Stoffler D: From the trap to the basket: getting to the bottom of the nuclear pore complex. Chromosoma. 2006, 115: 15-26. 10.1007/s00412-005-0037-1. Mattaj IW, Englmeier L: Nucleocytoplasmic transport: the soluble phase. Annu Rev Biochem. 1998, 67: 265-306. 10.1146/annurev.biochem.67.1.265. Görlich D, Kutay U: Transport between the cell nucleus and the cytoplasm. Annu Rev Cell Dev Biol. 1999, 15: 607-660. 10.1146/annurev.cellbio.15.1.607. Nakielny S, Dreyfuss G: Transport of proteins and RNAs in and out of the nucleus. Cell. 1999, 99: 677-90. 10.1016/S0092-8674(00)81666-9. Simos G, Grosshans H, Hurt E: Nuclear export of tRNA. Nuclear transport. Edited by: Weis K. 2002, Berlin: Springer-Verlag, 133-150. Izaurralde E: Nuclear export of messenger RNA. Nuclear transport. Edited by: Weis K. 2002, Berlin: Springer-Verlag, 133-150. Stoffler D, Goldie KN, Feja B, Aebi U: Calcium-mediated structural changes of native nuclear pore complexes monitored by time-lapse atomic force microscopy. J Mol Biol. 1999, 287: 741-52. 10.1006/jmbi.1999.2637. Stoffler D, Feja B, Fahrenkrog B, Walz J, Typke D, Aebi U: Cryo-electron tomography provides novel insights into nuclear pore architecture: implications for nucleocytoplasmic transport. J Mol Biol. 2003, 328: 119-30. 10.1016/S0022-2836(03)00266-3. Rout MP, Aitchison JD, Suprapto A, Hjertaas K, Zhao Y, Chait BT: The yeast nuclear pore complex: composition, architecture, and transport mechanism. J Cell Biol. 2000, 148: 635-51. 10.1083/jcb.148.4.635. Walther TC, Pickersgill HS, Cordes VC, Goldberg MW, Allen TD, Mattaj IW, Fornerod M: The cytoplasmic filaments of the nuclear pore complex are dispensable for selective nuclear protein import. J Cell Biol. 2002, 158: 63-77. 10.1083/jcb.200202088. Cronshaw JM, Krutchinsky AN, Zhang W, Chait BT, Matunis MJ: Proteomic analysis of the mammalian nuclear pore complex. J Cell Biol. 2002, 158: 915-927. 10.1083/jcb.200206106. Ben-Efraim I, Gerace L: Gradient of increasing affinity of importin beta for nucleoporins along the pathway of nuclear import. J Cell Biol. 2001, 152: 411-417. 10.1083/jcb.152.2.411. Macara IG: Transport into and out of the nucleus. Microbiol Mol Biol Rev. 2001, 65: 570-94. 10.1128/MMBR.65.4.570-594.2001. Ribbeck K, Gorlich D: The permeability barrier of nuclear pore complexes appears to operate via hydrophobic exclusion. EMBO J. 2002, 21: 2664-71. 10.1093/emboj/21.11.2664. Siomi MC, Eder PS, Kataoka N, Wan L, Liu Q, Dreyfuss G: Transportin-mediated nuclear import of heterogeneous nuclear RNP proteins. J Cell Biol. 1997, 138: 1181-1192. 10.1083/jcb.138.6.1181. Englmeier L, Olivo J-C, Mattaj IW: Receptor-mediated substrate translocation through the nuclear pore complex without nucleotide triphosphate hydrolysis. Curr Biol. 1999, 14: 30-41. 10.1016/S0960-9822(99)80044-X. Ribbeck K, Kutay U, Paraskeva E, Gorlich D: The translocation of transportin-cargo complexes through nuclear pores is independent of both Ran and energy. Curr Biol. 1999, 9: 47-50. 10.1016/S0960-9822(99)80046-3. Lyman SK, Guan T, Bednenko J, Wodrich H, Gerace L: Influence of cargo size on Ran and energy requirements for nuclear protein import. J Cell Biol. 2002, 159: 55-67. 10.1083/jcb.200204163. Schwoebel ED, Ho TH, Moore MS: The mechanism of inhibition of Ran-dependent nuclear transport by cellular ATP depletion. J Cell Biol. 2002, 157: 963-74. 10.1083/jcb.200111077. Fassati A, Gorlich D, Harrison I, Zaytseva L, Mingot JM: Nuclear import of HIV-1 intracellular reverse transcription complexes is mediated by importin 7. EMBO J. 2003, 22: 3675-85. 10.1093/emboj/cdg357. Feldherr CM, Akin D: The permeability of the nuclear envelope in dividing and nondividing cell cultures. J Cell Biol. 1990, 111: 1-8. 10.1083/jcb.111.1.1. Feldherr CM, Akin D: Signal-mediated nuclear transport in proliferating and growth-arrested BALB/c 3T3 cells. J Cell Biol. 1991, 115: 933-9. 10.1083/jcb.115.4.933. Feldherr CM, Akin D: Regulation of nuclear transport in proliferating and quiescent cells. Exp Cell Res. 1993, 205: 179-86. 10.1006/excr.1993.1073. Feldherr C, Akin D: Stimulation of nuclear import by simian virus 40-transformed cell extracts is dependent on protein kinase activity. Mol Cell Biol. 1995, 12: 7043-9. Kehlenbach RH, Gerace L: Phosphorylation of the nuclear transport machinery down-regulates nuclear protein import in vitro. J Biol Chem. 2000, 275: 17848-56. 10.1074/jbc.M001455200. Smith AE, Helenius A: How viruses enter animal cells. Science. 2004, 304: 237-42. 10.1126/science.1094823. Whittaker GR, Helenius A: Nuclear import and export of viruses and virus genomes. Virology. 1998, 246: 1-2. 10.1006/viro.1998.9165. Whittaker GR, Kann M, Helenius A: Viral entry into the nucleus. Annu Rev Cell Dev Biol. 2000, 16: 627-51. 10.1146/annurev.cellbio.16.1.627. Greber UF, Fassati A: Nuclear import of viral DNA genomes. Traffic. 2003, 4: 136-143. Hawkins RB: The influence of concentration of DNA on the radiosensitivity of mammalian cells. Int J Radiat Oncol Biol Phys. 2005, 63: 529-35. 10.1016/j.ijrobp.2005.05.055. Smith DE, Tans SJ, Smith SB, Grimes S, Anderson DL, Bustamante C: The bacteriophage straight phi29 portal motor can package DNA against a large internal force. Nature. 2001, 413: 748-52. 10.1038/35099581. Anderson LW, Klevjer-Anderson P, Liggitt HD: Susceptibility of blood-derived monocytes and macrophages to caprine arthritis-encephalitis virus. Infect Immun. 1983, 41: 837-40. Gendelman HE, Narayan O, Molineaux S, Clements JE, Ghotbi Z: Slow, persistent replication of lentiviruses: role of tissue macrophages and macrophage precursors in bone marrow. Proc Natl Acad Sci USA. 1985, 82: 7086-90. 10.1073/pnas.82.20.7086. Gendelman HE, Narayan O, Kennedy-Stoskopf S, Kennedy PG, Ghotbi Z, Clements JE, Stanley J, Pezeshkpour G: Tropism of sheep lentiviruses for monocytes: susceptibility to infection and virus gene expression increase during maturation of monocytes to macrophages. J Virol. 1986, 58: 67-74. Ryan S, Tiley L, McConnell I, Blacklaws B: Infection of dendritic cells by the Maedi-Visna lentivirus. J Virol. 2000, 74: 10096-10103. 10.1128/JVI.74.21.10096-10103.2000. Sellon DC, Perry ST, Coggins L, Fuller FJ: Wild-type equine infectious anemia virus replicates in vivo predominantly in tissue macrophages, not in peripheral blood monocytes. J Virol. 1992, 10: 5906-13. Ho DD, Rota TR, Hirsch MS: Infection of monocyte/macrophages by human T lymphotropic virus type III. J Clin Invest. 1986, 77: 1712-5. Gartner S, Markovits P, Markovitz DM, Kaplan MH, Gallo RC, Popovic M: The role of mononuclear phagocytes in HTLV-III/LAV infection. Science. 1986, 233: 215-9. 10.1126/science.3014648. Salahuddin SZ, Rose RM, Groopman JE, Markham PD, Gallo RC: Human T lymphotropic virus type III infection of human alveolar macrophages. Blood. 1986, 68: 281-284. Ringler DJ, Wyand MS, Walsh DG, MacKey JJ, Sehgal PK, Daniel MD, Desrosiers RC, King NW: The productive infection of alveolar macrophages by simian immunodeficiency virus. J Med Primatol. 1989, 18: 217-226. Ringler DJ, Wyand MS, Walsh DG, MacKey JJ, Chalifoux LV, Popovic M, Minassian AA, Sehgal PK, Daniel MD, Desrosiers RC, et al: Cellular localization of simian immunodeficiency virus in lymphoid tissues. I. Immunohistochemistry and electron microscopy. Am J Pathol. 1989, 134: 373-83. Weinberg JB, Matthews TJ, Cullen BR, Malim MH: Productive human immunodeficiency virus type 1 (HIV-1) infection of nonproliferating human monocytes. J Exp Med. 1991, 174: 1477-1482. 10.1084/jem.174.6.1477. Mehandru S, Poles MA, Tenner-Racz K, Horowitz A, Hurley A, Hogan C, Boden D, Racz P, Markowitz M: Primary HIV-1 infection is associated with preferential depletion of CD4+ T lymphocytes from effector sites in the gastrointestinal tract. J Exp Med. 2004, 200: 761-770. 10.1084/jem.20041196. Mattapallil JJ, Douek DC, Nishimura Y, Martin M, Roederer M: Massive infection and loss of memory CD4+ T cells in multiple tissues during acute SIV infection. Nature. 2005, 434: 1093-1097. 10.1038/nature03501. Li Q, Duan L, Estes JD, Ma ZM, Rourke T, Wang Y, Reilly C, Carlis J, Miller CJ, Haase AT: Peak SIV replication in resting memory CD4+ T cells depletes gut lamina propria CD4+ T cells. Nature. 2005, 434: 1148-52. Gonzalez-Scarano F, Martin-Garcia J: The neuropathogenesis of AIDS. Nat Rev Immunol. 2005, 5: 69-81. 10.1038/nri1527. Lewis P, Hensel M, Emerman M: Human immunodeficiency virus infection of cells arrested in the cell cycle. EMBO J. 1992, 11: 3053-8. Naldini L, Blomer U, Gage FH, Trono D, Verma IM: Efficient transfer, integration, and sustained long-term expression of the transgene in adult rat brains injected with a lentiviral vector. Proc Natl Acad Sci USA. 1996, 93: 11382-8. 10.1073/pnas.93.21.11382. Case SS, Price MA, Jordan CT, Yu XJ, Wang L, Bauer G, Haas DL, Xu D, Stripecke R, Naldini L, Kohn DB, Crooks GM: Stable transduction of quiescent CD34(+)CD38(-) human hematopoietic cells by HIV-1-based lentiviral vectors. Proc Natl Acad Sci USA. 1999, 96: 2988-93. 10.1073/pnas.96.6.2988. Katz RA, Greger JG, Boimel P, Skalka AM: Human immunodeficiency virus type 1 DNA nuclear import and integration are mitosis independent in cycling cells. J Virol. 2003, 77: 13412-7. 10.1128/JVI.77.24.13412-13417.2003. Mannioui A, Schiffer C, Felix N, Nelson E, Brussel A, Sonigo P, Gluckman JC, Canque B: Cell cycle regulation of human immunodeficiency virus type 1 integration in T cells: antagonistic effects of nuclear envelope breakdown and chromatin condensation. Virology. 2004, 329: 77-88. 10.1016/j.virol.2004.08.022. Groschel B, Bushman F: Cell cycle arrest in G2/M promotes early steps of infection by human immunodeficiency virus. J Virol. 2005, 79: 5695-704. 10.1128/JVI.79.9.5695-5704.2005. Miller DG, Adam MA, Miller AD: Gene transfer by retrovirus vectors occurs only in cells that are actively replicating at the time of infection. Mol Cell Biol. 1990, 10: 4239-42. Roe T, Reynolds TC, Yu G, Brown PO: Integration of murine leukemia virus DNA depends on mitosis. EMBO J. 1993, 12: 2099-108. Lewis PF, Emerman M: Passage through mitosis is required for oncoretroviruses but not for the human immunodeficiency virus. J Virol. 1994, 68: 510-6. Jarrosson-Wuilleme L, Goujon C, Bernaud J, Rigal D, Darlix JL, Cimarelli A: Transduction of nondividing human macrophages with gammaretrovirus-derived vectors. J Virol. 2006, 80: 1152-9. 10.1128/JVI.80.3.1152-1159.2006. Rubin H, Temin HM: A radiological study of cell-virus interaction in the Rous sarcoma. Virology. 1959, 7: 75-91. 10.1016/0042-6822(59)90178-3. Varmus HE, Padgett T, Heasley S, Simon G, Bishop JM: Cellular functions are required for the synthesis and integration of avian sarcoma virus-specific DNA. Cell. 1977, 11: 307-19. 10.1016/0092-8674(77)90047-2. Humphries EH, Glover C, Reichmann ME: Rous sarcoma virus infection of synchronized cells establishes provirus integration during S-phase DNA synthesis prior to cellular division. Proc Natl Acad Sci USA. 1981, 78: 2601-5. 10.1073/pnas.78.4.2601. Hatziioannou T, Goff SP: Infection of nondividing cells by Rous sarcoma virus. J Virol. 2001, 75: 9526-31. 10.1128/JVI.75.19.9526-9531.2001. Katz RA, Greger JG, Darby K, Boimel P, Rall GF, Skalka AM: Transduction of interphase cells by avian sarcoma virus. J Virol. 2002, 76: 5422-34. 10.1128/JVI.76.11.5422-5434.2002. Greger JG, Katz RA, Taganov K, Rall GF, Skalka AM: Transduction of terminally differentiated neurons by avian sarcoma virus. J Virol. 2004, 78: 4902-4906. 10.1128/JVI.78.9.4902-4906.2004. Saib A, Puvion-Dutilleul F, Schmid M, Peries J, de The H: Nuclear targeting of incoming human foamy virus Gag proteins involves a centriolar step. J Virol. 1997, 71: 1155-61. Linial ML: Foamy viruses are unconventional retroviruses. J Virol. 1999, 73: 1747-55. Mergia A, Chari S, Kolson DL, Goodenow MM, Ciccarone T: The efficiency of simian foamy virus vector type-1 (SFV-1) in nondividing cells and in human PBLs. Virology. 2001, 280: 243-52. 10.1006/viro.2000.0773. Trobridge G, Russell DW: Cell cycle requirements for transduction by foamy virus vectors compared to those of oncovirus and lentivirus vectors. J Virol. 2004, 78: 2327-35. 10.1128/JVI.78.5.2327-2335.2004. Josephson NC, Vassilopoulos G, Trobridge GD, Priestley GV, Wood BL, Papayannopoulou T, Russell DW: Transduction of human NOD/SCID-repopulating cells with both lymphoid and myeloid potential by foamy virus vectors. Proc Natl Acad Sci USA. 2002, 99: 8295-300. 10.1073/pnas.122131099. Bieniasz PD, Weiss RA, McClure MO: Cell cycle dependence of foamy retrovirus infection. J Virol. 1995, 69: 7295-9. Yamashita M, Emerman M: Capsid is a dominant determinant of retrovirus infectivity in nondividing cells. J Virol. 2004, 78: 5670-8. 10.1128/JVI.78.11.5670-5678.2004. Dismuke DJ, Aiken C: Evidence for a functional link between uncoating of the human immunodeficiency virus type 1 core and nuclear import of the viral preintegration complex. J Virol. 2006, 80: 3712-20. 10.1128/JVI.80.8.3712-3720.2006. Fassati A, Goff SP: Characterization of intracellular reverse transcription complexes of human immunodeficiency virus type 1. J Virol. 2001, 75: 3626-35. 10.1128/JVI.75.8.3626-3635.2001. Forshey BM, von Schwedler U, Sundquist WI, Aiken C: Formation of a human immunodeficiency virus type 1 core of optimal stability is crucial for viral replication. J Virol. 2002, 76: 5667-77. 10.1128/JVI.76.11.5667-5677.2002. Farnet CM, Haseltine WA: Determination of viral proteins present in the human immunodeficiency virus type 1 preintegration complex. J Virol. 1991, 65: 1910-5. Bukrinsky MI, Sharova N, McDonald TL, Pushkarskaya T, Tarpley WG, Stevenson M: 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 USA. 1993, 90: 6125-9. 10.1073/pnas.90.13.6125. Heinzinger NK, Bukinsky MI, Haggerty SA, Ragland AM, Kewalramani V, Lee MA, Gendelman HE, Ratner L, Stevenson M, Emerman M: The Vpr protein of human immunodeficiency virus type 1 influences nuclear localization of viral nucleic acids in nondividing host cells. Proc Natl Acad Sci USA. 1994, 91: 7311-5. 10.1073/pnas.91.15.7311. Miller MD, Farnet CM, Bushman FD: Human immunodeficiency virus type 1 preintegration complexes: studies of organization and composition. J Virol. 1997, 71: 5382-90. Karageorgos L, Li P, Burrell C: Characterization of HIV replication complexes early after cell-to-cell infection. AIDS Res Hum Retroviruses. 1993, 9: 817-23. Nermut MV, Fassati A: Structural analyses of purified human immunodeficiency virus type 1 intracellular reverse transcription complexes. J Virol. 2003, 77: 8196-206. 10.1128/JVI.77.15.8196-8206.2003. Jacqué JM, Triques K, Stevenson M: Modulation of HIV-1 replication by RNA interference. Nature. 2002, 418: 435-8. 10.1038/nature00896. Chiu YL, Soros VB, Kreisberg JF, Stopak K, Yonemoto W, Greene WC: Cellular APOBEC3G restricts HIV-1 infection in resting CD4+ T cells. Nature. 2005, 435: 108-14. 10.1038/nature03493. Joshi PJ, North TW, Prasad VR: Aptamers directed to HIV-1 reverse transcriptase display greater efficacy over small hairpin RNAs targeted to viral RNA in blocking HIV-1 replication. Mol Ther. 2005, 11: 677-86. 10.1016/j.ymthe.2005.01.013. Esterhout EM, ter Brake O, Berkhout B: The virion-associated incoming HIV-1 RNA genome is not targeted by RNA interference. Retrovirology. 2006, 4;3: 57-10.1186/1742-4690-3-57. Stremlau M, Perron M, Lee M, Li Y, Song B, Javanbakht H, Diaz-Griffero F, Anderson DJ, Sundquist WI, Sodroski J: Specific recognition and accelerated uncoating of retroviral capsids by the TRIM5alpha restriction factor. Proc Natl Acad Sci USA. 2006, 103: 5514-9. 10.1073/pnas.0509996103. Forshey BM, Shi J, Aiken C: Structural requirements for recognition of the human immunodeficiency virus type 1 core during host restriction in owl monkey cells. J Virol. 2005, 79: 869-75. 10.1128/JVI.79.2.869-875.2005. Perez-Caballero D, Hatziioannou T, Zhang F, Cowan S, Bieniasz PD: Restriction of human immunodeficiency virus type 1 by TRIM-CypA occurs with rapid kinetics and independently of cytoplasmic bodies, ubiquitin, and proteasome activity. J Virol. 2005, 79: 15567-72. 10.1128/JVI.79.24.15567-15572.2005. Risco C, Menendez-Arias L, Copeland TD, Pinto da Silva P, Oroszlan S: Intracellular transport of the murine leukemia virus during acute infection of NIH 3T3 cells: nuclear import of nucleocapsid protein and integrase. J Cell Sci. 1995, 108: 3039-50. Fassati A, Goff SP: Characterization of intracellular reverse transcription complexes of Moloney murine leukemia virus. J Virol. 1999, 73: 8919-25. Bowerman B, Brown PO, Bishop JM, Varmus HE: A nucleoprotein complex mediates the integration of retroviral DNA. Genes Dev. 1989, 3: 469-78. Yuan B, Fassati A, Yueh A, Goff SP: Characterization of Moloney murine leukemia virus p12 mutants blocked during early events of infection. J Virol. 2002, 76: 10801-10. 10.1128/JVI.76.21.10801-10810.2002. Yueh A, Leung J, Bhattacharyya S, Perrone LA, de los Santos K, Pu SY, Goff SP: Interaction of moloney murine leukemia virus capsid with Ubc9 and PIASy mediates SUMO-1 addition required early in infection. J Virol. 2006, 80: 342-52. 10.1128/JVI.80.1.342-352.2006. Mahajan R, Delphin C, Guan T, Gerace L, Melchior F: A small ubiquitin-related polypeptide involved in targeting RanGAP1 to nuclear pore complex protein RanBP2. Cell. 1997, 88: 97-107. 10.1016/S0092-8674(00)81862-0. Joseph J, Liu ST, Jablonski SA, Yen TJ, Dasso M: The RanGAP1-RanBP2 complex is essential for microtubule-kinetochore interactions in vivo. Curr Biol. 2004, 14: 611-7. 10.1016/j.cub.2004.03.031. Bukrinsky MI, Haggerty S, Dempsey MP, Sharova N, Adzhubel A, Spitz L, Lewis P, Goldfarb D, Emerman M, Stevenson M: A nuclear localization signal within HIV-1 matrix protein that governs infection of non-dividing cells. Nature. 1993, 365: 666-9. 10.1038/365666a0. von Schwedler U, Kornbluth RS, Trono D: 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 USA. 1994, 91: 6992-6. 10.1073/pnas.91.15.6992. Gallay P, Swingler S, Aiken C, Trono D: HIV-1 infection of nondividing cells: C-terminal tyrosine phosphorylation of the viral matrix protein is a key regulator. Cell. 1995, 80: 379-88. 10.1016/0092-8674(95)90488-3. Gallay P, Swingler S, Song J, Bushman F, Trono D: HIV nuclear import is governed by the phosphotyrosine-mediated binding of matrix to the core domain of integrase. Cell. 1995, 83: 569-76. 10.1016/0092-8674(95)90097-7. Bukrinskaya AG, Ghorpade A, Heinzinger NK, Smithgall TE, Lewis RE, Stevenson M: Phosphorylation-dependent human immunodeficiency virus type 1 infection and nuclear targeting of viral DNA. Proc Natl Acad Sci USA. 1996, 93: 367-71. 10.1073/pnas.93.1.367. Freed EO, Englund G, Maldarelli F, Martin MA: Phosphorylation of residue 131 of HIV-1 matrix is not required for macrophage infection. Cell. 1997, 88: 171-3. 10.1016/S0092-8674(00)81836-X. Freed EO, Englund G, Martin MA: Role of the basic domain of human immunodeficiency virus type 1 matrix in macrophage infection. J Virol. 1995, 69: 3949-54. Fouchier RA, Meyer BE, Simon JH, Fischer U, Malim MH: 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. 1997, 16: 4531-9. 10.1093/emboj/16.15.4531. 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: 387-95. 10.1006/excr.2000.5016. Mannioui A, Nelson E, Schiffer C, Felix N, Le Rouzic E, Benichou S, Gluckman JC, Canque B: Human immunodeficiency virus type 1 KK26-27 matrix mutants display impaired infectivity, circularization and integration but not nuclear import. Virology. 2005, 339: 21-30. 10.1016/j.virol.2005.05.023. Reil H, Bukovsky AA, Gelderblom HR, Gottlinger HG: Efficient HIV-1 replication can occur in the absence of the viral matrix protein. EMBO J. 1998, 17: 2699-708. 10.1093/emboj/17.9.2699. Dupont S, Sharova N, DeHoratius C, Virbasius CM, Zhu X, Bukrinskaya AG, Stevenson M, Green MR: A novel nuclear export activity in HIV-1 matrix protein required for viral replication. Nature. 1999, 402: 681-5. 10.1038/45272. Haffar OK, Popov S, Dubrovsky L, Agostini I, Tang H, Pushkarsky T, Nadler SG, Bukrinsky M: Two nuclear localization signals in the HIV-1 matrix protein regulate nuclear import of the HIV-1 pre-integration complex. J Mol Biol. 2000, 299: 359-68. 10.1006/jmbi.2000.3768. 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: 9825-30. 10.1073/pnas.94.18.9825. Le Rouzic E, Benichou S: The Vpr protein from HIV-1: distinct roles along the viral life cycle. Retrovirology. 2005, 2: 11-10.1186/1742-4690-2-11. Lu YL, Spearman P, Ratner L: Human immunodeficiency virus type 1 viral protein R localization in infected cells and virions. J Virol. 1993, 67: 6542-50. Di Marzio P, Choe S, Ebright M, Knoblauch R, Landau NR: Mutational analysis of cell cycle arrest, nuclear localization and virion packaging of human immunodeficiency virus type 1 Vpr. J Virol. 1995, 69: 7909-16. Mahalingam S, Collman RG, Patel M, Monken CE, Srinivasan A: Functional analysis of HIV-1 Vpr: identification of determinants essential for subcellular localization. Virology. 1995, 212: 331-9. 10.1006/viro.1995.1490. Fouchier RA, Meyer BE, Simon JH, Fischer U, Albright AV, Gonzalez-Scarano F, Malim MH: Interaction of the human immunodeficiency virus type 1 Vpr protein with the nuclear pore complex. J Virol. 1998, 72: 6004-13. Jenkins Y, McEntee M, Weis K, Greene WC: Characterization of HIV-1 vpr nuclear import: analysis of signals and pathways. J Cell Biol. 1998, 143: 875-85. 10.1083/jcb.143.4.875. Vodicka MA, Koepp DM, Silver PA, Emerman M: HIV-1 Vpr interacts with the nuclear transport pathway to promote macrophage infection. Genes Dev. 1998, 12: 175-85. Le Rouzic E, Mousnier A, Rustum C, Stutz F, Hallberg E, Dargemont C, Benichou S: Docking of HIV-1 Vpr to the nuclear envelope is mediated by the interaction with the nucleoporin hCG1. J Biol Chem. 2002, 277: 45091-8. 10.1074/jbc.M207439200. Gallay P, Stitt V, Mundy C, Oettinger M, Trono D: Role of the karyopherin pathway in human immunodeficiency virus type 1 nuclear import. J Virol. 1996, 70: 1027-32. Paxton W, Connor RI, Landau NR: Incorporation of Vpr into human immunodeficiency virus type 1 virions: requirement for the p6 region of gag and mutational analysis. J Virol. 1993, 67: 7229-37. Jenkins Y, Sanchez PV, Meyer BE, Malim MH: Nuclear export of human immunodeficiency virus type 1 Vpr is not required for virion packaging. J Virol. 2001, 75: 8348-52. 10.1128/JVI.75.17.8348-8352.2001. Sherman MP, de Noronha CM, Eckstein LA, Hataye J, Mundt P, Williams SA, Neidleman JA, Goldsmith MA, Greene WC: Nuclear export of Vpr is required for efficient replication of human immunodeficiency virus type 1 in tissue macrophages. J Virol. 2003, 77: 7582-9. 10.1128/JVI.77.13.7582-7589.2003. McDonald D, Vodicka MA, Lucero G, Svitkina TM, Borisy GG, Emerman M, Hope TJ: Visualization of the intracellular behavior of HIV in living cells. J Cell Biol. 2002, 159: 441-52. 10.1083/jcb.200203150. Popov S, Rexach M, Ratner L, Blobel G, Bukrinsky M: Viral protein R regulates docking of the HIV-1 preintegration complex to the nuclear pore complex. J Biol Chem. 1998, 273: 13347-52. 10.1074/jbc.273.21.13347. de Noronha CM, Sherman MP, Lin HW, Cavrois MV, Moir RD, Goldman RD, Greene WC: Dynamic disruptions in nuclear envelope architecture and integrity induced by HIV-1 Vpr. Science. 2001, 294: 1105-8. 10.1126/science.1063957. Connor RI, Chen BK, Choe S, Landau NR: Vpr is required for efficient replication of human immunodeficiency virus type-1 in mononuclear phagocytes. Virology. 1995, 206: 935-44. 10.1006/viro.1995.1016. Zufferey R, Nagy D, Mandel RJ, Naldini L, Trono D: Multiply attenuated lentiviral vector achieves efficient gene delivery in vivo. Nat Biotechnol. 1997, 15: 871-5. 10.1038/nbt0997-871. Fletcher TM, Brichacek B, Sharova N, Newman MA, Stivahtis G, Sharp PM, Emerman M, Hahn BH, Stevenson M: Nuclear import and cell cycle arrest functions of the HIV-1 Vpr protein are encoded by two separate genes in HIV-2/SIV(SM). EMBO J. 1996, 15: 6155-65. Gibbs JS, Lackner AA, Lang SM, Simon MA, Sehgal PK, Daniel MD, Desrosiers RC: Progression to AIDS in the absence of a gene for vpr or vpx. J Virol. 1995, 69: 2378-83. Hirsch VM, Sharkey ME, Brown CR, Brichacek B, Goldstein S, Wakefield J, Byrum R, Elkins WR, Hahn BH, Lifson JD, Stevenson M: Vpx is required for dissemination and pathogenesis of SIV(SM) PBj: evidence of macrophage-dependent viral amplification. Nat Med. 1998, 4: 1401-8. 10.1038/3992. 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: 7119-26. 10.1128/JVI.74.15.7119-7126.2000. 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: 18102-7. 10.1074/jbc.M009029200. Ao Z, Fowke KR, Cohen EA, 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: 62-10.1186/1742-4690-2-62. 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: 11563-73. 10.1128/JVI.78.21.11563-11573.2004. 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: 4795-806. 10.1128/JVI.74.10.4795-4806.2000. 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: 33528-39. 10.1074/jbc.M303594200. Hearps AC, Jans DA: HIV-1 integrase is capable of targeting DNA to the nucleus via an importin alpha/beta dependent mechanism. Biochem J. 2006, 398: 475-484. 10.1042/BJ20060466. Arnold M, Nath A, Hauber J, Kehlenbach RH: Multiple importins function as nuclear transport receptors for the Rev protein of the human immunodeficiency virus type I. J Biol Chem. 2006, 281: 20883-90. 10.1074/jbc.M602189200. Wodrich H, Cassany A, D'Angelo MA, Guan T, Nemerow G, Gerace L: Adenovirus core protein pVII is translocated into the nucleus by multiple import receptor pathways. J Virol. 2006, 80: 9608-18. 10.1128/JVI.00850-06. Jakel S, Gorlich D: Importin beta, transportin, RanBP5 and RanBP7 mediate nuclear import of ribosomal proteins in mammalian cells. EMBO J. 1998, 17: 4491-502. 10.1093/emboj/17.15.4491. 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: 372-81. 10.1074/jbc.M209278200. Llano M, Vanegas M, Fregoso O, Saenz D, Chung S, Peretz M, Poeschla EM: 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: 9524-37. 10.1128/JVI.78.17.9524-9537.2004. Llano M, Delgado S, Vanegas M, Poeschla EM: Lens epithelium-derived growth factor/p75 prevents proteasomal degradation of HIV-1 integrase. J Biol Chem. 2004, 279: 55570-7. 10.1074/jbc.M408508200. 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: 33421-9. 10.1074/jbc.M404700200. 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 NLS-independent chromatin tethering. J Cell Sci. 2005, 118: 1733-43. 10.1242/jcs.02299. Vandekerckhove L, Christ F, Van Maele B, De Rijck J, Gijsbers R, Van den Haute C, Witvrouw M, Debyser Z: Transient and stable knockdown of the integrase cofactor LEDGF/p75 reveals its role in the replication cycle of human immunodeficiency virus. J Virol. 2006, 80: 1886-96. 10.1128/JVI.80.4.1886-1896.2006. Cherepanov P, Sun ZY, Rahman S, Maertens G, Wagner G, Engelman A: Solution structure of the HIV-1 integrase-binding domain in LEDGF/p75. Nat Struct Mol Biol. 2005, 12: 526-32. 10.1038/nsmb937. Devroe E, Engelman A, Silver PA: Intracellular transport of human immunodeficiency virus type 1 integrase. J Cell Sci. 2003, 116: 4401-8. 10.1242/jcs.00747. Kukolj G, Jones KS, Skalka AM: Subcellular localization of avian sarcoma virus and human immunodeficiency virus type 1 integrases. J Virol. 1997, 71: 843-7. Gao K, Butler SL, Bushman F: Human immunodeficiency virus type 1 integrase: arrangement of protein domains in active cDNA complexes. EMBO J. 2001, 20: 3565-76. 10.1093/emboj/20.13.3565. Bouyac-Bertoia M, Dvorin JD, Fouchier RA, Jenkins Y, Meyer BE, Wu LI, Emerman M, Malim MH: HIV-1 infection requires a functional integrase NLS. Mol Cell. 2001, 7: 1025-35. 10.1016/S1097-2765(01)00240-4. Dvorin JD, Bell P, Maul GG, Yamashita M, Emerman M, Malim MH: Reassessment of the roles of integrase and the central DNA flap in human immunodeficiency virus type 1 nuclear import. J Virol. 2002, 76: 12087-96. 10.1128/JVI.76.23.12087-12096.2002. Limon A, Nakajima N, Lu R, Ghory HZ, Engelman A: Wild-type levels of nuclear localization and human immunodeficiency virus type 1 replication in the absence of the central DNA flap. J Virol. 2002, 76: 12078-86. 10.1128/JVI.76.23.12078-12086.2002. Limon A, Devroe E, Lu R, Ghory HZ, Silver PA, 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: 10598-607. 10.1128/JVI.76.21.10598-10607.2002. Lu R, Limon A, Devroe E, Silver PA, Cherepanov P, Engelman A: Class II integrase mutants with changes in putative nuclear localization signals are primarily blocked at a postnuclear entry step of human immunodeficiency virus type 1 replication. J Virol. 2004, 78: 12735-46. 10.1128/JVI.78.23.12735-12746.2004. Yamashita M, Emerman M: The cell cycle independence of HIV infections is not determined by known karyophilic viral elements. PLoS Pathog. 2005, 1 (3): e18-10.1371/journal.ppat.0010018. Charneau P, Alizon M, Clavel F: A second origin of DNA plus-strand synthesis is required for optimal human immunodeficiency virus replication. J Virol. 1992, 66: 2814-20. Charneau P, Clavel F: A single-stranded gap in human immunodeficiency virus unintegrated linear DNA defined by a central copy of the polypurine tract. J Virol. 1991, 65: 2415-21. Zennou V, Petit C, Guetard D, Nerhbass U, Montagnier L, Charneau P: HIV-1 genome nuclear import is mediated by a central DNA flap. Cell. 2000, 101: 173-85. 10.1016/S0092-8674(00)80828-4. Follenzi A, Ailles LE, Bakovic S, Geuna M, Naldini L: Gene transfer by lentiviral vectors is limited by nuclear translocation and rescued by HIV-1 pol sequences. Nat Genet. 2000, 25: 217-22. 10.1038/76095. Zennou V, Serguera C, Sarkis C, Colin P, Perret E, Mallet J, Charneau P: The HIV-1 DNA flap stimulates HIV vector-mediated cell transduction in the brain. Nat Biotechnol. 2001, 19: 446-50. 10.1038/88115. Manganini M, Serafini M, Bambacioni F, Casati C, Erba E, Follenzi A, Naldini L, Bernasconi S, Gaipa G, Rambaldi A, Biondi A, Golay J, Introna M: A human immunodeficiency virus type 1 pol gene-derived sequence (cPPT/CTS) increases the efficiency of transduction of human nondividing monocytes and T lymphocytes by lentiviral vectors. Hum Gene Ther. 2002, 13: 1793-807. 10.1089/104303402760372909. Van Maele B, De Rijck J, De Clercq E, Debyser Z: Impact of the central polypurine tract on the kinetics of human immunodeficiency virus type 1 vector transduction. J Virol. 2003, 77: 4685-94. 10.1128/JVI.77.8.4685-4694.2003. Ao Z, Yao X, Cohen EA: Assessment of the role of the central DNA flap in human immunodeficiency virus type 1 replication by using a single-cycle replication system. J Virol. 2004, 78: 3170-7. 10.1128/JVI.78.6.3170-3177.2004. Heyman T, Wilhelm M, Wilhelm FX: The central PPT of the yeast retrotransposon Ty1 is not essential for transposition. J Mol Biol. 2003, 331: 315-20. 10.1016/S0022-2836(03)00812-X. Arhel N, Munier S, Souque P, Mollier K, Charneau P: Nuclear import defect of human immunodeficiency virus type 1 DNA flap mutants is not dependent on the viral strain or target cell type. J Virol. 2006, 80: 10262-9. 10.1128/JVI.00974-06. Adam SA, Marr RS, Gerace L: Nuclear protein import in permeabilized mammalian cells requires soluble cytoplasmic factors. J Cell Biol. 1990, 111: 807-16. 10.1083/jcb.111.3.807. Adam SA, Gerace L: Cytosolic proteins that specifically bind nuclear location signals are receptors for nuclear import. Cell. 1991, 66: 837-47. 10.1016/0092-8674(91)90431-W. Moore MS, Blobel G: The two steps of nuclear import, targeting to the nuclear envelope and translocation through the nuclear pore, require different cytosolic factors. Cell. 1992, 69: 939-50. 10.1016/0092-8674(92)90613-H. Gorlich D, Prehn S, Laskey RA, Hartmann E: Isolation of a protein that is essential for the first step of nuclear protein import. Cell. 1994, 79: 767-78. 10.1016/0092-8674(94)90067-1. Zielske SP, 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: 11541-6. 10.1128/JVI.79.17.11541-11546.2005. Vandegraaff N, Devroe E, Turlure F, Silver PA, Engelman A: Biochemical and genetic analyses of integrase-interacting proteins lens epithelium-derived growth factor (LEDGF)/p75 and hepatoma-derived growth factor related protein 2 (HRP2) in preintegration complex function and HIV-1 replication. Virology. 2006, 346: 415-26. 10.1016/j.virol.2005.11.022. Zaitseva L, Mayers R, Fassati A: tRNAs promote nuclear import of HIV-1 intracellular reverse transcription complexes. PloS Biol. 4 (10): e332-10.1371/journal.pbio.0040332. Takano A, Endo T, Yoshihisa T: tRNA actively shuttles between the nucleus and cytosol in yeast. Science. 2005, 309: 140-142. 10.1126/science.1113346. Shaheen HH, Hopper AK: Retrograde movement of tRNAs from the cytoplasm to the nucleus in Saccaromyces cervisiae. Proc Natl Acad Sci USA. 2005, 102: 11290-11295. 10.1073/pnas.0503836102. Erkmann JA, Kutay U: Nuclear export of mRNA: from the site of transcription to the cytoplasm. Exp Cell Res. 2004, 296: 12-20. 10.1016/j.yexcr.2004.03.015. Yang J, Bogerd HP, Wang PJ, Page DC, Cullen BR: Two closely related human nuclear export factors utilize entirely distinct export pathways. Mol Cell. 2001, 8: 397-406. 10.1016/S1097-2765(01)00303-3. Yu JH, Schaffer DV: High-throughput, library-based selection of a murine leukemia virus variant to infect nondividing cells. J Virol. 2006, 80: 8981-8. 10.1128/JVI.00615-06.