HIV-1 Vpr-a still "enigmatic multitasker"

Frontiers in Microbiology

Volumn 5, Issue MAR, 2014, Pages

  Guenzel, Carolin A ^a   Hérate, Cécile ^a   Benichou, Serge ^a  

^a INSTITUT COCHIN   (France)

Author keywords

Apoptosis; Cell cycle; HIV 1 Vpr; Nuclear import; Reverse transcription

Indexed keywords

AMINO ACID; GAG PROTEIN; VIRUS DNA; VPR PROTEIN;

APOPTOSIS; CELL CYCLE; CELL CYCLE ARREST; HUMAN IMMUNODEFICIENCY VIRUS 1; LIFE CYCLE STAGE; MACROPHAGE; NONHUMAN; NUCLEAR IMPORT; REVERSE TRANSCRIPTION; REVIEW; SIMIAN IMMUNODEFICIENCY VIRUS; VIRUS MORPHOLOGY;

EID: 84897942744     PISSN: None     EISSN: 1664302X     Source Type: Journal    
DOI: 10.3389/fmicb.2014.00127     Document Type: Review

References (188)

1. Abbas, W. (2013). T-Cell Signaling in HIV-1 Infection. Open Virol. J. 7, 57-71. doi: 10.2174/1874357920130621001.
2. Accola, M. A., Ohagen, A., and Göttlinger, H. G. (2000). Isolation of human immunodeficiency virus type 1 cores: retention of vpr in the absence of P6(gag). J. Virol. 74, 6198-6202. doi: 10.1128/JVI.74.13.6198-6202.2000.
3. Ances, B. M., and Ellis, R. J. (2007). Dementia and neurocognitive disorders due to HIV-1 infection. Semin. Neurol. 27, 86-92. doi: 10.1055/s-2006-956759.
4. Andersen, J. L., DeHart, J. L., Zimmerman, E. S., Ardon, O., Kim, B., Jacquot, G., et al. (2006). HIV-1 Vpr-induced apoptosis is cell cycle dependent and requires Bax but not ANT. PLoS Pathog. 2:e127. doi: 10.1371/journal.ppat.0020127.
5. Andersen, J. L., Zimmerman, E. S., DeHart, J. L., Murala, S., Ardon, O., Blackett, J., et al. (2005). ATR and GADD45alpha mediate HIV-1 Vpr-induced apoptosis. Cell Death Differ. 12, 326-334. doi: 10.1038/sj.cdd.4401565.
6. Angers, S., Li, T., Yi, X., MacCoss, M. J., Moon, R. T., and Zheng, N. (2006). Molecular architecture and assembly of the DDB1-CUL4A ubiquitin ligase machinery. Nature 443, 590-593. doi: 10.1038/nature05175.
7. Bachand, F., Yao, X. J., Hrimech, M., Rougeau, N., and Cohen, E. A. (1999). Incorporation of Vpr into human immunodeficiency virus type 1 requires a direct interaction with the P6 domain of the P55 gag precursor. J. Biol. Chem. 274, 9083-9091. doi: 10.1074/jbc.274.13.9083.
8. Balliet, J. W., Kolson, D. L., Eiger, G., Kim, F. M., McGann, K. A., Srinivasan, A., et al. (1994) Distinct effects in primary macrophages and lymphocytes of the human immunodeficiency virus type 1 accessory genes vpr, vpu, and nef: mutational analysis of a primary HIV-1 isolate. Virology 200, 623-631. doi: 10.1006/viro.1994.1225.
9. Barnitz, R. A., Chaigne-Delalande, B., Bolton, D. L., and Lenardo, M. J. (2011). Exposed Hydrophobic residues in human immunodeficiency virus type 1 Vpr Helix-1 are important for cell cycle arrest and cell death. PLoS ONE 6:e24924. doi: 10.1371/journal.pone.0024924.
10. Belzile, J.-P., Duisit, G., Rougeau, N., Mercier, J., Finzi, A., and Cohen, E. A. (2007). HIV-1 Vpr-mediated G2 arrest involves the DDB1-CUL4AVPRBP E3 ubiquitin ligase. PLoS Pathog. 3:e85. doi: 10.1371/journal.ppat.0030085.
11. Belzile, J.-P., Richard, J., Rougeau, N., Xiao, Y., and Cohen, E. A. (2010). HIV-1 Vpr induces the K48-linked polyubiquitination and proteasomal degradation of target cellular proteins to activate ATR and promote G2 arrest. J. Virol. 84, 3320-3330. doi: 10.1128/JVI.02590-09.
12. Bolton, D. L., Barnitz, R. A., Sakai, K., and Lenardo, M. J. (2008). 14-3-3 theta binding to cell cycle regulatory factors is enhanced by HIV-1 Vpr. Biol. Direct 3, 17. doi: 10.1186/1745-6150-3-17.
13. Bolton, D. L., and Lenardo, M. J. (2007). Vpr cytopathicity independent of G2/M cell cycle arrest in human immunodeficiency virus type 1-infected CD4+ T Cells. J. Virol. 81, 8878-8890. doi: 10.1128/JVI.00122-07.
14. Bruns, K., Fossen, T., Wray, V., Henklein, P., Tessmer, U., and Schubert, U. (2003). Structural characterization of the HIV-1 Vpr N terminus: evidence of Cis/trans-proline Isomerism. J. Biol. Chem. 278, 43188-43201. doi: 10.1074/jbc.M305413200.
15. Bukrinsky, M. I., Sharova, N., McDonald, T. L., Pushkarskaya, T., Tarpley, W. G., and 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, 6125-6129. doi: 10.1073/pnas.90.13.6125.
16. Busca, A., Saxena, M., and Kumar, A. (2012). Critical role for antiapoptotic Bcl-xL and Mcl-1 in human macrophage survival and cellular IAP1/2 (cIAP1/2) in resistance to HIV-Vpr-induced apoptosis. J. Biol. Chem. 287, 15118-15133. doi: 10.1074/jbc.M111.312660.
17. Casey Klockow, L., Sharifi, H. J., Wen, X., Flagg, M., Furuya, A. K., Nekorchuk, M., et al. (2013) The HIV-1 protein Vpr targets the endoribonuclease Dicer for proteasomal degradation to boost macrophage infection. Virology 444, 191-202. doi: 10.1016/j.virol.2013.06.010.
18. Checroune, F., Yao, X. J., Göttlinger, H. G., Bergeron, D., and Cohen, E. A. (1995) Incorporation of Vpr into human immunodeficiency virus type 1: role of conserved regions within the P6 domain of Pr55gag. J. Acquir. Immune Defic. Syndr. Hum. Retrovirol. 10, 1-7. doi: 10.1097/00042560-199509000-00001.
19. Chen, M., Elder, R. T., Yu, M., O'Gorman, M. G., Selig, L., Benarous, R., et al. (1999). Mutational analysis of Vpr-induced G2Arrest, nuclear localization, and cell death in fission yeast. J. Virol. 73, 3236-3245.
20. Chen, R., Le Rouzic, E., Kearney, J. A., Mansky, L. M., and Benichou, S. (2004). Vpr-mediated incorporation of UNG2 into HIV-1 particles is required to modulate the virus mutation rate and for replication in macrophages. J. Biol. Chem. 279, 28419-28425. doi: 10.1074/jbc.M403875200.
21. Chen, R., Wang, H., and Mansky, L. M. (2002). Roles of uracil-DNA glycosylase and dUTPase in virus replication. J. Gen. Virol. 83, 2339-2345.
22. Cliby, W. A., Lewis, K. A., Lilly, K. K., and Kaufmann, S. H. (2002). S Phase and G2 Arrests induced by topoisomerase i poisons are dependent on ATR kinase function. J. Biol. Chem. 277, 1599-1606. doi: 10.1074/jbc.M106287200.
23. Coeytaux, E., Coulaud, D., Le Cam, E., Danos, O., and Kichler, A. (2003). The cationic amphipathic alpha-helix of HIV-1 viral protein R (Vpr) binds to nucleic acids, permeabilizes membranes, and efficiently transfects cells. J. Biol. Chem. 278, 18110-18116. doi: 10.1074/jbc.M300248200.
24. Cohen, E. A., Dehni, G., Sodroski, J. G., and Haseltine, W. A. (1990). Human immunodeficiency virus Vpr product is a virion-associated regulatory protein. J. Virol. 64, 3097-3099.
25. Connor, R. I., Chen, B. K., Choe, S., and Landau, N. R. (1995). Vpr is required for efficient replication of human immunodeficiency virus Type-1 in mononuclear phagocytes. Virology 206, 935-944. doi: 10.1006/viro.1995.1016.
26. Cronshaw, J. M., Krutchinsky, A. N., Zhang, W., Chait, B. T., and Matunis, M. J. (2002). Proteomic analysis of the mammalian nuclear pore complex. J. Cell Biol. 158, 915-927. doi: 10.1083/jcb.200206106.
27. Cui, J., Tungaturthi, P. K., Ayyavoo, V., Ghafouri, M., Ariga, H., Khalili, K., et al. (2006). The role of Vpr in the regulation of HIV-1 gene expression. Cell Cycle 5, 2626-2638. doi: 10.4161/cc.5.22.3442.
28. Cummins, N. W., and Badley, A. D. (2010). Mechanisms of HIV-associated lymphocyte apoptosis: 2010. Cell Death Dis. 1, e99. doi: 10.1038/cddis.2010.77.
29. Dehart, J. L., and Planelles, V. (2008). Human immunodeficiency virus type 1 Vpr links proteasomal degradation and checkpoint activation. J. Virol. 82, 1066-1072. doi: 10.1128/JVI.01628-07.
30. DeHart, J. L., Zimmerman, E. S., Ardon, O., Monteiro-Filho, C. M., Argañaraz, E. R., and Planelles, V. (2007). HIV-1 Vpr activates the G2 checkpoint through manipulation of the ubiquitin proteasome system. Virol. J. 4, 57. doi: 10.1186/1743-422X-4-57.
31. de Noronha, C. M. C., Sherman, M. P., Lin, H. W., Cavrois, M. V., Moir, R. D., Goldman, R. D., and Greene, W. C. (2001). Dynamic disruptions in nuclear envelope architecture and integrity induced by HIV-1 Vpr. Science 294, 1105-1108. doi: 10.1126/science.1063957.
32. Depienne, C., Roques, P., Créminon, C., Fritsch, L., Casseron, R., Dormont, D., et al. (2000). Cellular distribution and karyophilic properties of matrix, integrase, and Vpr proteins from the human and simian immunodeficiency viruses. Exp. Cell Res. 260, 387-395. doi: 10.1006/excr.2000.5016.
33. De Rocquigny, H., Caneparo, A., Delaunay, T., Bischerour, J., Mouscadet, J. F., and Roques, B. P. (2000). Interactions of the C-terminus of viral protein R with nucleic acids are modulated by its N-terminus. Eur. J. Biochem. 267, 3654-3660. doi: 10.1046/j.1432-1327.2000.01397.x.
34. De Silva, F. S., and Moss, B. (2008). Effects of vaccinia virus uracil DNA glycosylase catalytic site and deoxyuridine triphosphatase deletion mutations individually and together on replication in active and quiescent cells and pathogenesis in mice. Virol. J. 5, 145. doi: 10.1186/1743-422X-5-145.
35. Dong, C. Z., De Rocquigny, H., Rémy, E., Mellac, S., Fournié-Zaluski, M. C., and Roques, B. P. (1997). Synthesis and biological activities of fluorescent acridine-containing HIV-1 nucleocapsid proteins for investigation of nucleic acid-NCp7 interactions. J. Pept. Res. 50, 269-278. doi: 10.1111/j.1399-3011.1997.tb01468.x.
36. Eckstein, D. A., Sherman, M. P., Penn, M. L., Chin, P. S., De Noronha, C. M., Greene, W. C., et al. (2001). HIV-1 Vpr enhances viral burden by facilitating infection of tissue macrophages but not nondividing CD4+ T cells. J. Exp. Med. 194, 1407-1419. doi: 10.1084/jem.194.10.1407.
37. Eldin, P., Chazal, N., Fenard, D., Bernard, E., Guichou, J.-F., and Briant, L. (2013). Vpr expression abolishes the capacity of HIV-1 infected cells to repair uracilated DNA. Nucleic Acids Res. 42, 1698-1710. doi: 10.1093/nar/gkt974.
38. Farnet, C. M., and Haseltine, W. A. (1991). Determination of viral proteins present in the human immunodeficiency virus type 1 preintegration complex. J. Virol. 65, 1910-1915.
39. Fassati, A., and Goff, S. P. (2001). Characterization of intracellular reverse transcription complexes of human immunodeficiency virus type 1. J. Virol. 75, 3626-3635. doi: 10.1128/JVI.75.8.3626-3635.2001.
40. Fassati, A., Görlich, D., Harrison, I., Zaytseva, L., and Mingot, J.-M. (2003). Nuclear import of HIV-1 intracellular reverse transcription complexes is mediated by importin 7. EMBO J. 22, 3675-3685. doi: 10.1093/emboj/cdg357.
41. Ferrucci, A., Nonnemacher, M. R., and Wigdahl, B. (2013). Extracellular HIV-1 viral protein R affects astrocytic glyceraldehyde 3-phosphate dehydrogenase activity and neuronal survival. J. Neurovirol. 19, 239-253. doi: 10.1007/s13365-013-0170-1.
42. Fouchier, R. A., Meyer, B. E., Simon, J. H., Fischer, U., Albright, A. V., González-Scarano, F., et al. (1998). Interaction of the human immunodeficiency virus type 1 Vpr protein with the nuclear pore complex. J. Virol. 72, 6004-6013.
43. Fourati, S., Malet, I., Binka, M., Boukobza, S., Wirden, M., Sayon, S., et al. (2010). Partially active HIV-1 Vif alleles facilitate viral escape from specific antiretrovirals. AIDS 24, 2313-2321. doi: 10.1097/QAD.0b013e32833e515a.
44. Fourati, S., Malet, I., Guenzel, C. A., Soulie, C., Maidou-Peindara, P., Morand-Joubert, L., et al. (2012). E17A mutation in HIV-1 Vpr confers resistance to didanosine in association with thymidine analog mutations. Antiviral Res. 93, 167-174. doi: 10.1016/j.antiviral.2011.11.008.
45. Fritz, J. V., Didier, P., Clamme, J.-P., Schaub, E., Muriaux, D., Cabanne, C., et al. (2008). Direct Vpr-Vpr interaction in cells monitored by two photon fluorescence correlation spectroscopy and fluorescence lifetime imaging. Retrovirology 5, 87. doi: 10.1186/1742-4690-5-87.
46. Fritz, J. V., Dujardin, D., Godet, J., Didier, P., De Mey, J., Darlix, J.-L., et al. (2010). HIV-1 Vpr oligomerization but not that of gag directs the interaction between Vpr and Gag. J. Virol. 84, 1585-1596. doi: 10.1128/JVI.01691-09.
47. Gallay, P., Stitt, V., Mundy, C., Oettinger, M., and Trono, D. (1996). Role of the karyopherin pathway in human immunodeficiency virus type 1 nuclear import. J. Virol. 70, 1027-1032.
48. Ghiotto, F., Fais, F., and Bruno, S. (2010). BH3-only proteins: the death-puppeteer's wires. Cytometry A 77, 11-21. doi: 10.1002/cyto.a.20819.
49. Goff, S. P. (2001). Intracellular trafficking of retroviral genomes during the early phase of infection: viral exploitation of cellular pathways. J. Gene. Med. 3, 517-528. doi: 10.1002/1521-2254(200111)3:6<517::AID-JGM234>3.0.CO;2-E.
50. Goh, W. C., Rogel, M. E., Kinsey, C. M., Michael, S. F., Fultz, P. N., Nowak, M. A., et al. (1998). HIV-1 Vpr increases viral expression by manipulation of the cell cycle: a mechanism for selection of Vpr in vivo. Nat. Med. 4, 65-71. doi: 10.1038/nm0198-065.
51. Greber, U. F., and Fassati, A. (2003). Nuclear import of viral DNA genomes. Traffic 4, 136-143. doi: 10.1034/j.1600-0854.2003.00114.x.
52. Guenzel, C. A., Hérate, C., Le Rouzic, E., Maidou-Peindara, P., Sadler, H. A., Rouyez, M.-C., et al. (2012). Recruitment of the nuclear form of uracil DNA glycosylase into virus particles participates in the full infectivity of HIV-1. J. Virol. 86, 2533-2544. doi: 10.1128/JVI.05163-11.
53. Harezlak, J., Buchthal, S., Taylor, M., Schifitto, G., Zhong, J., Daar, E., et al. (2011). Persistence of HIV-associated cognitive impairment, inflammation, and neuronal injury in era of highly active antiretroviral treatment. AIDS 25, 625-633. doi: 10.1097/QAD.0b013e3283427da7.
54. Hattori, N., Michaels, F., Fargnoli, K., Marcon, L., Gallo, R. C., and Franchini, G. (1990). The human immunodeficiency virus type 2 Vpr gene is essential for productive infection of human macrophages. Proc. Natl. Acad. Sci. U.S.A. 87, 8080-8084. doi: 10.1073/pnas.87.20.8080.
55. He, J., Choe, S., Walker, R., Di Marzio, P., Morgan, D. O., and Landau, N. R. (1995). Human immunodeficiency virus type 1 viral protein R (Vpr) arrests cells in the G2 phase of the cell cycle by inhibiting p34cdc2 activity. J. Virol. 69, 6705-6711.
56. He, Y. J., McCall, C. M., Hu, J., Zeng, Y., and Xiong, Y. (2006). DDB1 functions as a linker to recruit receptor WD40 proteins to CUL4-ROC1 ubiquitin ligases. Genes Dev. 20, 2949-2954. doi: 10.1101/gad.1483206.
57. Heinzinger, N. K., Bukinsky, M. I., Haggerty, S. A., Ragland, A. M., Kewalramani, V., Lee, M. A., 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, 7311-7315. doi: 10.1073/pnas.91.15.7311.
58. Hemonnot, B., Cartier, C., Gay, B., Rebuffat, S., Bardy, M., Devaux, C., et al. (2004). The host cell MAP kinase ERK-2 regulates viral assembly and release by phosphorylating the P6gag protein of HIV-1. J. Biol. Chem 279, 32426-32434. doi: 10.1074/jbc.M313137200.
59. Hermeking, H., and Benzinger, A. (2006). 14-3-3 proteins in cell cycle regulation. Semin. Cancer Biol. 16, 183-192. doi: 10.1016/j.semcancer.2006.03.002.
60. Higa, L. A., Wu, M., Ye, T., Kobayashi, R., Sun, H., and Zhang, H. (2006a). CUL4-DDB1 ubiquitin ligase interacts with multiple WD40-repeat proteins and regulates histone methylation. Nat. Cell Biol. 8, 1277-1283. doi: 10.1038/ncb1490.
61. Higa, L. A., Yang, X., Zheng, J., Banks, D., Wu, M., Ghosh, P., et al. (2006b). Involvement of CUL4 ubiquitin E3 ligases in regulating CDK inhibitors Dacapo/p27Kip1 and cyclin E degradation. Cell Cycle 5, 71-77. doi: 10.4161/cc.5.1.2266.
62. Hoch, J., Lang, S. M., Weeger, M., Stahl-Hennig, C., Coulibaly, C., Dittmer, U., et al. (1995). Vpr deletion mutant of simian immunodeficiency virus induces AIDS in rhesus monkeys. J. Virol. 69, 4807-4813.
63. Hrecka, K., Gierszewska, M., Srivastava, S., Kozaczkiewicz, L., Swanson, S. K., Florens, L., et al. (2007). Lentiviral Vpr usurps Cul4-DDB1[VprBP] E3 ubiquitin ligase to modulate cell cycle. Proc. Natl. Acad. Sci. U.S.A. 104, 11778-11783. doi: 10.1073/pnas.0702102104.
64. Jacotot, E., Ferri, K. F., El Hamel, C., Brenner, C., Druillennec, S., Hoebeke, J., et al. (2001). Control of mitochondrial membrane permeabilization by adenine nucleotide translocator interacting with HIV-1 viral protein rR and Bcl-2. J. Exp. Med. 193, 509-519. doi: 10.1084/jem.193.4.509.
65. Jacotot, E., Ravagnan, L., Loeffler, M., Ferri, K. F., Vieira, H. L. A., Zamzami, N., et al. (2000). The HIV-1 viral protein R induces apoptosis via a direct effect on the mitochondrial permeability transition pore. J. Exp. Med. 191, 33. doi: 10.1084/jem.191.1.33.
66. Jacquot, G., Le Rouzic, E., David, A., Mazzolini, J., Bouchet, J., Bouaziz, S., et al. (2007). Localization of HIV-1 Vpr to the nuclear envelope: impact on Vpr functions and virus replication in macrophages. Retrovirology 4, 84. doi: 10.1186/1742-4690-4-84.
67. Jenkins, Y., McEntee, M., Weis, K., and Greene, W. C. (1998). Characterization of HIV-1 vpr nuclear import: analysis of signals and pathways. J. Cell Biol. 143, 875-885. doi: 10.1083/jcb.143.4.875.
68. Jenkins, Y., Pornillos, O., Rich, R. L., Myszka, D. G., Sundquist, W. I., and Malim, M. H. (2001a). Biochemical analyses of the interactions between human immunodeficiency virus type 1 Vpr and p6(Gag). J. Virol. 75, 10537-10542. doi: 10.1128/JVI.75.21.10537-10542.2001.
69. Jenkins, Y., Sanchez, P. V., Meyer, B. E., and Malim, M. H. (2001b). Nuclear export of human immunodeficiency virus type 1 Vpr is not required for virion packaging. J. Virol. 75, 8348-8352. doi: 10.1128/JVI.75.17.8348-8352.2001.
70. Jin, J., Arias, E. E., Chen, J., Harper, J. W., and Walter, J. C. (2006). A family of diverse Cul4-Ddb1-interacting proteins includes Cdt2, which is required for S phase destruction of the replication factor Cdt1. Mol. Cell 23, 709-721. doi: 10.1016/j.molcel.2006.08.010.
71. Jones, G. J., Barsby, N. L., Cohen, E. A., Holden, J., Harris, K., Dickie, P., et al. (2007). HIV-1 Vpr causes neuronal apoptosis and in vivo neurodegeneration. J. Neurosci. 27, 3703-3711. doi: 10.1523/JNEUROSCI.5522-06.2007.
72. Jones, K. L., Roche, M., Gantier, M. P., Begum, N. A., Honjo, T., Caradonna, S., et al. (2010). X4 and R5 HIV-1 have distinct post-entry requirements for uracil DNA glycosylase during infection of primary cells. J. Biol. Chem. 285, 18603-18614. doi: 10.1074/jbc.M109.090126.
73. Jowett, J. B., Planelles, V., Poon, B., Shah, N. P., Chen, M. L., and Chen, I. S. (1995). The human immunodeficiency virus type 1 vpr gene arrests infected T cells in the G2 + M phase of the cell cycle. J. Virol. 69, 6304-6313.
74. Kaiser, S. M., and Emerman, M. (2006). Uracil DNA glycosylase is dispensable for human immunodeficiency virus type 1 replication and does not contribute to the antiviral effects of the cytidine deaminase apobec3G. J. Virol. 80, 875-882. doi: 10.1128/JVI.80.2.875-882.2006.
75. Kamata, M., Watanabe, N., Nagaoka, Y., and Chen, I. S. Y. (2008). Human immunodeficiency virus type 1 Vpr binds to the N lobe of the Wee1 kinase domain and enhances kinase activity for CDC2. J. Virol. 82, 5672-5682. doi: 10.1128/JVI.01330-07.
76. Kamiyama, T., Miura, T., and Takeuchi, H. (2013). His-Trp cation-p interaction and its structural role in an A-helical dimer of HIV-1 Vpr protein. Biophys. Chem. 173-174, 8-14. doi: 10.1016/j.bpc.2013.01.004.
77. Kichler, A., Pages, J. C., Leborgne, C., Druillennec, S., Lenoir, C., Coulaud, D., et al. (2000). Efficient DNA transfection mediated by the C-terminal domain of human immunodeficiency virus type 1 viral protein R. J. Virol. 74, 5424-5431. doi: 10.1128/JVI.74.12.5424-5431.2000.
78. Kino, T., Gragerov, A., Valentin, A., Tsopanomihalou, M., Ilyina-Gragerova, G., Erwin-Cohen, R., et al. (2005). Vpr protein of human immunodeficiency virus type 1 binds to 14-3-3 proteins and facilitates complex formation with Cdc25C: implications for cell cycle arrest. J. Virol. 79, 2780-2787. doi: 10.1128/JVI.79.5.2780-2787.2005.
79. Kitamura, K., Wang, Z., Chowdhury, S., Simadu, M., Koura, M., and Muramatsu, M. (2013) Uracil DNA glycosylase counteracts APOBEC3G-induced hypermutation of hepatitis B viral genomes: excision repair of covalently closed circular DNA. PLoS Pathog. 9:e1003361. doi: 10.1371/journal.ppat.1003361.
80. Klarmann, G. J., Chen, X., North, T. W., and Preston, B. D. (2003). Incorporation of uracil into minus strand DNA affects the specificity of plus strand synthesis initiation during lentiviral reverse transcription. J. Biol. Chem. 278, 7902-7909. doi: 10.1074/jbc.M207223200.
81. Knight, D. M., Flomerfelt, F. A., and Ghrayeb, J. (1987). Expression of the art/trs protein of HIV and study of its role in viral envelope synthesis. Science 236, 837-840. doi: 10.1126/science.3033827.
82. Kondo, E., and Göttlinger, H. G. (1996). A conserved LXXLF sequence is the major determinant in P6gag required for the incorporation of human immunodeficiency virus type 1 Vpr. J. Virol. 70, 159-164.
83. Koundrioukoff, S., Polo, S., and Almouzni, G. (2004). Interplay between chromatin and cell cycle checkpoints in the context of ATR/ATM-dependent checkpoints. DNA Repair (Amst.) 3, 969-978. doi: 10.1016/j.dnarep.2004.03.010.
84. Kudoh, A., Takahama, S., Sawasaki, T., Ode, H., Yokoyama, M., Okayama, A., et al. (2014). The phosphorylation of HIV-1 gag by atypical protein kinase C facilitates viral infectivity by promoting Vpr incorporation into virions. Retrovirology 11, 9. doi: 10.1186/1742-4690-11-9.
85. Laguette, N., Brégnard, C., Hue, P., Basbous, J., Yatim, A., Larroque, M., et al. (2014). Premature activation of the SLX4 complex by Vpr promotes G2/M arrest and escape from innate immune sensing. Cell 156, 134-145. doi: 10.1016/j.cell.2013.12.011.
86. Lang, S. M., Weeger, M., Stahl-Hennig, C., Coulibaly, C., Hunsmann, G., Müller, J., et al. (1993). Importance of Vpr for infection of rhesus monkeys with simian immunodeficiency virus. J. Virol. 67, 902-912.
87. Langevin, C., Maidou-Peindara, P., Aas, P. A., Jacquot, G., Otterlei, M., Slupphaug, G., et al. (2009). Human immunodeficiency virus type 1 Vpr modulates cellular expression of UNG2 via a negative transcriptional effect. J. Virol. 83, 10256-10263. doi: 10.1128/JVI.02654-08.
88. Langlois, M.-A., and Neuberger, M. S. (2008). Human APOBEC3G can restrict retroviral infection in avian cells and acts independently of both UNG and SMUG1. J. Virol. 82, 4660-4664. doi: 10.1128/JVI.02469-07.
89. Lecossier, D., Bouchonnet, F., Clavel, F., and Hance, A. J. (2003). Hypermutation of HIV-1 DNA in the absence of the Vif protein. Science 300, 1112. doi: 10.1126/science.1083338.
90. Le Rouzic, E., Belaïdouni, N., Estrabaud, E., Morel, M., Rain, J.-C., Transy, C., et al. (2007). HIV1 Vpr arrests the cell cycle by recruiting DCAF1/VprBP, a receptor of the Cul4-DDB1 ubiquitin ligase. Cell Cycle 6, 182-188. doi: 10.4161/cc.6.2.3732.
91. Le Rouzic, E., and Benichou, S. (2005). The Vpr protein from HIV-1: distinct roles along the viral life cycle. Retrovirology 2, 11. doi: 10.1186/1742-4690-2-11.
92. Le Rouzic, E., Mousnier, A., Rustum, C., Stutz, F., Hallberg, E., Dargemont, C., 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, 45091-45098. doi: 10.1074/jbc.M207439200.
93. Li, G., Park, H. U., Liang, D., and Zhao, R. Y. (2010). Cell cycle G2/M arrest through an S phase-dependent mechanism by HIV-1 viral protein R. Retrovirology 7, 59. doi: 10.1186/1742-4690-7-59.
94. Liang, G., Kitamura, K., Wang, Z., Liu, G., Chowdhury, S., Fu, W., et al. (2013). RNA editing of hepatitis B virus transcripts by activation-induced cytidine deaminase. Proc. Natl. Acad. Sci. U.S.A. 110, 2246-2251. doi: 10.1073/pnas.1221921110.
95. Liu, H.Wu, X., Xiao, H., and Kappes, J. C. (1999). Targeting human immunodeficiency virus (HIV) type 2 integrase protein into HIV type 1. J. Virol. 73, 8831-8836.
96. Loeb, J. E., Weitzman, M. D., and Hope, T. J. (2002). Enhancement of green fluorescent protein expression in adeno-associated virus with the woodchuck hepatitis virus post-transcriptional regulatory element. Methods Mol. Biol. 183, 331-340. doi: 10.1089/10430349950016942.
97. Lopez-Girona, A., Furnari, B., Mondesert, O., and Russell, P. (1999). Nuclear localization of Cdc25 is regulated by DNA damage and a 14-3-3 protein. Nature 397, 172-175. doi: 10.1038/16488.
98. Lyonnais, S., Gorelick, R. J., Heniche-Boukhalfa, F., Bouaziz, S., Parissi, V., Mouscadet, J.-F., et al. (2013). A protein ballet around the viral genome orchestrated by HIV-1 reverse transcriptase leads to an architectural switch: from nucleocapsid-condensed RNA to Vpr-bridged DNA. Virus Res. 171, 287-303. doi: 10.1016/j.virusres.2012.09.008.
99. Mahalingam, S., Ayyavoo, V., Patel, M., Kieber-Emmons, T., and Weiner, D. B. (1997). Nuclear import, virion incorporation, and cell cycle arrest/differentiation are mediated by distinct functional domains of human immunodeficiency virus type 1 Vpr. J. Virol. 71, 6339-6347.
100. Majumder, B., Venkatachari, N. J., Schafer, E. A., Janket, M. L., and Ayyavoo, V. (2007). Dendritic cells infected with vpr-positive human immunodeficiency virus type 1 induce CD8+ T-cell apoptosis via upregulation of tumor necrosis factor alpha. J. Virol. 81, 7388-7399. doi: 10.1128/JVI.00893-06.
101. Mangeat, B., Turelli, P., Caron, G., Friedli, M., Perrin, L., and Trono, D. (2003). Broad antiretroviral defence by human APOBEC3G through lethal editing of nascent reverse transcripts. Nature 424, 99-103. doi: 10.1038/nature01709.
102. Mansky, L. M. (1996). The mutation rate of human immunodeficiency virus type 1 is influenced by the Vpr Gene. Virology 222, 391-400. doi: 10.1006/viro.1996.0436.
103. Mansky, L. M., Preveral, S., Selig, L., Benarous, R., and Benichou, S. (2000). The interaction of Vpr with uracil DNA glycosylase modulates the human immunodeficiency virus type 1 in vivo mutation rate. J. Virol. 74, 7039-7047. doi: 10.1128/JVI.74.15.7039-7047.2000.
104. Mansky, L. M., and Yemin, H. M. (1995). Lower in vivo mutation rate of human immunodeficiency virus type 1 than that predicted from the fidelity of purified reverse transcriptase. J. Virol. 69, 5087-5094.
105. Mariani, R., Chen, D., Schröfelbauer, B., Navarro, F., König, R., Bollmann, B., et al. (2003). Species-specific exclusion of APOBEC3G from HIV-1 virions by Vif. Cell 114, 21-31. doi: 10.1016/S0092-8674(03)00515-4.
106. Marzio, P. D., Choe, S., Ebright, M., Knoblauch, R., and Landau, N. R. (1995). Mutational analysis of cell cycle arrest, nuclear localization and virion packaging of human immunodeficiency virus type 1 Vpr. J. Virol. 69, 7909-7916.
107. McDonald, D., Vodicka, M. A., Lucero, G., Svitkina, T. M., Borisy, G. G., Emerman, M., et al. (2002). Visualization of the intracellular behavior of HIV in living cells. J. Cell Biol. 159, 441-452. doi: 10.1083/jcb.200203150.
108. Mer, G., Bochkarev, A., Chazin, W. J., and Edwards, A. M. (2000). Three-dimensional structure and function of replication protein A. Cold Spring Harb. Symp. Quant. Biol. 65, 193-200. doi: 10.1101/sqb.2000.65.193.
109. Miller, M. D., Farnet, C. M., and Bushman, F. D. (1997). Human immunodeficiency virus type 1 preintegration complexes: studies of organization and composition. J. Virol. 71, 5382-5390.
110. Mishra, S., Mishra, J. P., and Kumar, A. (2007). Activation of JNK-dependent pathway is required for HIV viral protein R-induced apoptosis in human monocytic cells: involvement of antiapoptotic BCL2 and c-IAP1 genes. J. Biol. Chem. 282, 4288-4300. doi: 10.1074/jbc.M608307200.
111. Morellet, N., Bouaziz, S., Petitjean, P., and Roques, B. P. (2003). NMR structure of the HIV-1 regulatory protein VPR. J. Mol. Biol. 327, 215-227. doi: 10.1016/S0022-2836(03)00060-3.
112. Nagelhus, T. A., Haug, T., Singh, K. K., Keshav, K. F., Skorpen, F., Otterlei, M., et al. (1997). A sequence in the N-terminal region of human uracil-DNA glycosylase with homology to XPA interacts with the C-terminal part of the 34-kDa subunit of replication protein A. J. Biol. Chem. 272, 6561-6566. doi: 10.1074/jbc.272.10.6561.
113. Nekorchuk, M. D., Sharifi, H. J., Furuya, A. K., Jellinger, R., and de Noronha, C. M. (2013) HIV relies on neddylation for ubiquitin ligase-mediated functions. Retrovirology 10, 138. doi: 10.1186/1742-4690-10-138.
114. Nermut, M. V., and Fassati, A. (2003). Structural analyses of purified human immunodeficiency virus type 1 intracellular reverse transcription complexes. J. Virol. 77, 8196-8206. doi: 10.1128/JVI.77.15.8196-8206.2003.
115. Nishizawa, M., Kamata, M., Katsumata, R., and Aida, Y. (2000a). A carboxy-terminally truncated form of the human immunodeficiency virus type 1 Vpr protein induces apoptosis via G(1) cell cycle arrest. J. Virol. 74, 6058-6067. doi: 10.1128/JVI.74.13.6058-6067.2000.
116. Nishizawa, M., Kamata, M., Mojin, T., Nakai, Y., and Aida, Y. (2000b). Induction of apoptosis by the Vpr protein of human immunodeficiency virus type 1 occurs independently of G(2) arrest of the cell cycle. Virology 276, 16-26. doi: 10.1006/viro.2000.0534.
117. Nitahara-Kasahara, Y., Kamata, M., Yamamoto, T., Zhang, X., Miyamoto, Y., Muneta, K., et al. (2007). Novel nuclear import of Vpr promoted by importin alpha is crucial for human immunodeficiency virus type 1 replication in macrophages. J. Virol. 81, 5284-5293. doi: 10.1128/JVI.01928-06.
118. Ogawa, K., Shibata, R., Kiyomasu, T., Higuchi, I., Kishida, Y., Ishimoto, A., et al. (1989). Mutational analysis of the human immunodeficiency virus Vpr open reading frame. J. Virol. 63, 4110-4114.
119. Otterlei, M., Warbrick, E., Nagelhus, T. A., Haug, T., Slupphaug, G., Akbari, M., et al. (1999). Post-replicative base excision repair in replication foci. EMBO J. 18, 3834-3844. doi: 10.1093/emboj/18.13.3834.
120. Paillart, J. C., and Göttlinger, H. G. (1999). Opposing effects of human immunodeficiency virus type 1 matrix mutations support a myristyl switch model of gag membrane targeting. J. Virol. 73, 2604-2612.
121. Planelles, V., and Benichou, S. (2009). Vpr and its interactions with cellular proteins. Curr. Top. Microbiol. Immunol. 339, 177-200. doi: 10.1007/978-3-642-02175-6_9.
122. Planelles, V., Jowett, J. B., Li, Q. X., Xie, Y., Hahn, B., and Chen, I. S. (1996). Vpr-induced cell cycle arrest is conserved among primate lentiviruses. J. Virol. 70, 2516-2524.
123. Pomerantz, R. J. (2000). Residual HIV-1 replication. Biomed. Pharmacother. 54, 13-15. doi: 10.1016/S0753-3322(00)88635-7.
124. Poon, B., and Chen, I. S. (2003) Human immunodeficiency virus type 1 (HIV-1) Vpr enhances expression from unintegrated HIV-1 DNA. J. Virol. 77, 3962-3972. doi: 10.1128/JVI.77.7.3962-3972.2003.
125. Popov, S., Rexach, M., Ratner, L., Blobel, G., and Bukrinsky, M. (1998). Viral protein R regulates docking of the HIV-1 preintegration complex to the nuclear pore complex. J. Biol. Chem. 273, 13347-13352. doi: 10.1074/jbc.273.21.13347.
126. Priet, S., Gros, N., Navarro, J.-M., Boretto, J., Canard, B., Quérat, G., et al. (2005). HIV-1-associated uracil DNA glycosylase activity controls dUTP misincorporation in viral DNA and is essential to the HIV-1 life cycle. Mol. Cell 17, 479-490. doi: 10.1016/j.molcel.2005.01.016.
127. Priet, S., Navarro, J. M., Gros, N., Querat, G., and Sire, J. (2003) Functional role of HIV-1 virion-associated uracil DNA glycosylase 2 in the correction of G:U mispairs to G:C pairs. J. Biol. Chem. 278, 4566-4571. doi: 10.1074/jbc.M209311200.
128. Ramboarina, S., Druillennec, S., Morellet, N., Bouaziz, S., and Roques, B. P. (2004). Target Specificity of Human Immunodeficiency Virus Type 1 NCp7 Requires an Intact Conformation of Its CCHC N-terminal Zinc Finger. J. Virol. 78, 6682-6687. doi: 10.1128/JVI.78.12.6682-6687.2004.
129. Re, F., Braaten, D., Franke, E. K., and Luban, J. (1995). Human immunodeficiency virus type 1 Vpr arrests the cell cycle in G2 by inhibiting the activation of p34cdc2-cyclin B. J. Virol. 69, 6859-6864.
130. Reiss, P., Lange, J. M., de Ronde, A., de Wolf, F., Dekker, J., Danner, S. A., et al. (1990). Antibody response to viral proteins U (vpu) and R (vpr) in HIV-1-infected individuals. J. Acquir. Immune Defic. Syndr. 3, 115-122.
131. Richard, J., Sindhu, S., Pham, T. N. Q., Belzile, J.-P., and Cohen, E. A. (2010). HIV-1 Vpr up-regulates expression of ligands for the activating NKG2D receptor and promotes NK cell-mediated killing. Blood 115, 1354-1363. doi: 10.1182/blood-2009-08-237370.
132. Rogel, M. E., Wu, L. I., and Emerman, M. (1995). The human immunodeficiency virus type 1 vpr gene prevents cell proliferation during chronic infection. J. Virol. 69, 882-888.
133. Rom, I., Deshmane, S. L., Mukerjee, R., Khalili, K., Amini, S., and Sawaya, B. E. (2009). HIV-1 Vpr deregulates calcium secretion in neural cells. Brain Res. 1275, 81-86. doi: 10.1016/j.brainres.2009.03.024.
134. Romani, B., and Cohen, E. A. (2012). Lentivirus Vpr and Vpx accessory proteins usurp the cullin4-DDB1 (DCAF1) E3 ubiquitin ligase. Curr. Opin. Virol. 2, 755-763. doi: 10.1016/j.coviro.2012.09.010.
135. Roshal, M., Kim, B., Zhu, Y., Nghiem, P., and Planelles, V. (2003). Activation of the ATR-mediated DNA damage response by the HIV-1 viral protein R. J. Biol. Chem. 278, 25879-25886. doi: 10.1074/jbc.M303948200.
136. Rout, M. P., and Aitchison, J. D. (2001). The nuclear pore complex as a transport machine. J. Biol. Chem. 276, 16593-16596. doi: 10.1074/jbc.R100015200.
137. Salgado, G. F., Vogel, A., Marquant, R., Feller, S. E., Bouaziz, S., and Alves, I. D. (2009). The Role of membranes in the organization of HIV-1 Gag P6 and Vpr: P6 shows high affinity for membrane bilayers which substantially increases the interaction between P6 and Vpr. J. Med. Chem. 52, 7157-7162. doi: 10.1021/jm901106t.
138. Sato, K., Misawa, N., Iwami, S., Satou, Y., Matsuoka, M., Ishizaka, Y., et al. (2013) HIV-1 Vpr accelerates viral replication during acute infection by exploitation of proliferating CD4(+) T Cells in vivo. PLoS Pathog. 9:e1003812. doi: 10.1371/journal.ppat.1003812.
139. Sawaya, B. E., Khalili, K., Mercer, W. E., Denisova, L., and Amini, S. (1998). Cooperative actions of HIV-1 Vpr and p53 modulate viral gene transcription. J. Biol. Chem. 273, 20052-20057. doi: 10.1074/jbc.273.32.20052.
140. Schang, L. M. (2003). The cell cycle, cyclin-dependent kinases, and viral infections: new horizons and unexpected connections. Prog. Cell Cycle Res. 5, 103-124.
141. Schrofelbauer, B., Hakata, Y., and Landau, N. R. (2007). HIV-1 Vpr function is mediated by interaction with the damage-specific DNA-binding protein DDB1. Proc. Natl. Acad. Sci. U.S.A. 104, 4130-4135. doi: 10.1073/pnas.0610167104.
142. Schrofelbauer, B., Yu, Q., Zeitlin, S. G., and Landau, N. R. (2005). Human immunodeficiency virus type 1 Vpr induces the degradation of the UNG and SMUG uracil-DNA glycosylases. J. Virol. 79, 10978-10987. doi: 10.1128/JVI.79.17.10978-10987.2005.
143. Schüler, W., Wecker, L., De Rocquigny, H., Baudat, Y., Sire, J., and Roques, B. P. (1999). NMR structure of the (52-96) C-terminal domain of the HIV-1 regulatory protein Vpr: molecular insights into its biological functions. J. Mol. Biol. 285, 2105-2117. doi: 10.1006/jmbi.1998.2381.
144. Segura-Totten, M., and Wilson, K. L. (2001). Virology. HIV-breaking the rules for nuclear entry. Science 294, 1016-1017. doi: 10.1126/science.1066729.
145. Selig, L., Pages, J. C., Tanchou, V., Prévéral, S., Berlioz-Torrent, C., Liu, L. X., et al. (1999). Interaction with the P6 domain of the gag precursor mediates incorporation into virions of Vpr and Vpx proteins from primate lentiviruses. J. Virol. 73, 592-600.
146. Sheehy, A. M., Gaddis, N. C., Choi, J. D., and Malim, M. H. (2002). Isolation of a human gene that inhibits HIV-1 infection and is suppressed by the viral Vif protein. Nature 418, 646-650. doi: 10.1038/nature00939.
147. Sherman, M. P., de Noronha, C. M. C., Eckstein, L. A., Hataye, J., Mundt, P., Williams, S. A. F., et al. (2003). Nuclear export of Vpr is required for efficient replication of human immunodeficiency virus type 1 in tissue macrophages. J. Virol. 77, 7582-7589. doi: 10.1128/JVI.77.13.7582-7589.2003.
148. Sherman, M. P., de Noronha, C. M. C., Heusch, M. I., Greene, S., and Greene, W. C. (2001). Nucleocytoplasmic shuttling by human immunodeficiency virus type 1 Vpr. J. Virol. 75, 1522-1532. doi: 10.1128/JVI.75.3.1522-1532.2001.
149. Sherman, M. P., de Noronha, C. M. C., Williams, S. A., and Greene, W. C. (2002). Insights into the biology of HIV-1 viral protein R. DNA Cell Biol. 21, 679-688. doi: 10.1089/104454902760330228.
150. Shimura, M., Toyoda, Y., Iijima, K., Kinomoto, M., Tokunaga, K., Yoda, K., et al. (2011). Epigenetic displacement of HP1 from heterochromatin by HIV-1 Vpr causes premature sister chromatid separation. J. Cell Biol. 194, 721-735. doi: 10.1083/jcb.201010118.
151. Singh, S. P., Tomkowicz, B., Lai, D., Cartas, M., Mahalingam, S., Kalyanaraman, V. S., et al. (2000). Functional role of residues corresponding to helical domain II (amino Acids 35 to 46) of human immunodeficiency virus type 1 Vpr. J. Virol. 74, 10650-10657. doi: 10.1128/JVI.74.22.10650-10657.2000.
152. Sørensen, C. S., and Syljuåsen, R. G. (2012). Safeguarding genome integrity: the checkpoint kinases ATR, CHK1 and WEE1 restrain CDK activity during normal DNA replication. Nucleic Acids Res. 40, 477-486. doi: 10.1093/nar/gkr697.
153. Sörgel, S., Fraedrich, K., Votteler, J., Thomas, M., Stamminger, T., and Schubert, U. (2012). Perinuclear localization of the HIV-1 regulatory protein Vpr is important for induction of G2-arrest. Virology 432, 444-451. doi: 10.1016/j.virol.2012.06.027.
154. Stark, L. A., and Hay, R. T. (1998). Human immunodeficiency virus type 1 (HIV-1) viral protein R (Vpr) interacts with Lys-tRNA synthetase: implications for priming of HIV-1 reverse transcription. J. Virol. 72, 3037-3044.
155. Steffens, C. M., and Hope, T. J. (2003). Localization of CD4 and CCR5 in living cells. J. Virol. 77, 4985-4991. doi: 10.1128/JVI.77.8.4985-4991.2003.
156. Steffy, K., and Wong-Staal, F. (1991). Genetic regulation of human immunodeficiency virus. Microbiol. Rev. 55, 193-205.
157. Stewart, S. A., Poon, B., Jowett, J. B., and Chen, I. S. (1997). Human immunodeficiency virus type 1 Vpr induces apoptosis following cell cycle arrest. J. Virol. 71, 5579-5592.
158. Stewart, S. A., Poon, B., Jowett, J. B., Xie, Y., and Chen, I. S. (1999). Lentiviral delivery of HIV-1 Vpr protein induces apoptosis in transformed cells. Proc. Natl. Acad. Sci. U.S.A. 96, 12039-12043. doi: 10.1073/pnas.96.21.12039.
159. Stivahtis, G. L., Soares, M. A., Vodicka, M. A., Hahn, B. H., and Emerman, M. (1997). Conservation and host specificity of Vpr-mediated cell cycle arrest suggest a fundamental role in primate lentivirus evolution and biology. J. Virol. 71, 4331-4338.
160. Stopak, K., de Noronha, C., Yonemoto, W., and Greene, W. C. (2003) HIV-1 Vif blocks the antiviral activity of APOBEC3G by impairing both its translation and intracellular stability. Mol. Cell. 12, 591-601. doi: 10.1016/S1097-2765(03)00353-8.
161. Sugasawa, K., Okuda, Y., Saijo, M., Nishi, R., Matsuda, N., Chu, G., et al. (2005). UV-induced ubiquitylation of XPC protein mediated by UV-DDB-ubiquitin ligase complex. Cell 121, 387-400. doi: 10.1016/j.cell.2005.02.035.
162. Suzuki, T., Yamamoto, N., Nonaka, M., Hashimoto, Y., Matsuda, G., Takeshima, S., et al. (2009). Inhibition of human immunodeficiency virus type 1 (HIV-1) nuclear import via Vpr-importin alpha interactions as a novel HIV-1 therapy. Biochem. Biophys. Res. Commun. 380, 838-843. doi: 10.1016/j.bbrc.2009.01.180.
163. Tan, L., Ehrlich, E., and Yu, X.-F. (2007). DDB1 and Cul4A are required for human immunodeficiency virus type 1 Vpr-induced G2 arrest. J. Virol. 81, 10822-10830. doi: 10.1128/JVI.01380-07.
164. Thierry, S., Marechal, V., Rosenzwajg, M., Sabbah, M., Redeuilh, G., Nicolas, J.-C., et al. (2004). Cell cycle arrest in G2 induces human immunodeficiency virus type 1 transcriptional activation through histone acetylation and recruitment of CBP, NF-κ B, and c-Jun to the long terminal repeat promoter. J. Virol. 78, 12198-12206. doi: 10.1128/JVI.78.22.12198-12206.2004.
165. Trinité, B., Ohlson, E. C., Voznesensky, I., Rana, S. P., Chan, C. N., Mahajan, S., et al. (2013). An HIV-1 replication pathway utilizing reverse transcription products that fail to integrate. J. Virol. 87, 12701-12720. doi: 10.1128/JVI.01939-13.
166. Tristem, M., Marshall, C., Karpas, A., and Hill, F. (1992). Evolution of the primate lentiviruses: evidence from Vpx and Vpr. EMBO J. 11, 3405-3012.
167. Venkatachari, N. J., Walker, L. A., Tastan, O., Le, T., Dempsey, T. M., Li, Y., et al. (2010). Human immunodeficiency virus type 1 Vpr: oligomerization is an essential feature for its incorporation into virus particles. Virology 7, 119. doi: 10.1186/1743-422X-7-119.
168. Vodicka, M. A., Koepp, D. M., Silver, P. A., and Emerman, M. (1998). HIV-1 Vpr interacts with the nuclear transport pathway to promote macrophage infection. Genes Dev. 12, 175-185. doi: 10.1101/gad.12.2.175.
169. Wang, H., Zhai, L., Xu, J., Joo, H.-Y., Jackson, S., Erdjument-Bromage, H., et al. (2006). Histone H3 and H4 ubiquitylation by the CUL4-DDB-ROC1 ubiquitin ligase facilitates cellular response to DNA damage. Mol. Cell 22, 383-394. doi: 10.1016/j.molcel.2006.03.035.
170. Wang, L., Mukherjee, S., Jia, F., Narayan, O., and Zhao, L. J. (1995). Interaction of virion protein Vpr of human immunodeficiency virus type 1 with cellular transcription factor Sp1 and trans-activation of viral long terminal repeat. J. Biol. Chem. 270, 25564-25569. doi: 10.1074/jbc.270.43.25564.
171. Wang, L., Mukherjee, S., Narayan, O., and Zhao, L. J. (1996). Characterization of a Leucine-zipper-like domain in Vpr protein of human immunodeficiency virus type 1. Gene 178, 7-13. doi: 10.1016/0378-1119(96)00312-5.
172. Ward, J., Davis, Z., DeHart, J., Zimmerman, E., Bosque, A., Brunetta, E., et al. (2009). HIV-1 Vpr triggers natural killer cell-mediated lysis of infected cells through activation of the ATR-mediated DNA damage response. PLoS Pathog. 5:e1000613. doi: 10.1371/journal.ppat.1000613.
173. Weil, A. F., Ghosh, D., Zhou, Y., Seiple, L., McMahon, M. A., Spivak, A. M., et al. (2013). Uracil DNA glycosylase initiates degradation of HIV-1 cDNA containing misincorporated dUTP and prevents viral integration. Proc. Natl. Acad. Sci. U.S.A. 110, E448-E457. doi: 10.1073/pnas.1219702110.
174. Welker, R., Hohenberg, H., Tessmer, U., Huckhagel, C., and Kräusslich, H. G. (2000). Biochemical and structural analysis of isolated mature cores of human immunodeficiency virus type 1. J. Virol. 74, 1168-1177. doi: 10.1128/JVI.74.3.1168-1177.2000.
175. Wen, X., Duus, K. M., Friedrich, T. D., and de Noronha, C. M. C. (2007). The HIV1 protein Vpr acts to promote G2 cell cycle arrest by engaging a DDB1 and Cullin4A-containing ubiquitin ligase complex using VprBP/DCAF1 as an adaptor. J. Biol. Chem. 282, 27046-27057. doi: 10.1074/jbc.M703955200.
176. Wu, X., Liu, H., Xiao, H., Conway, J. A., Hehl, E., Kalpana, G. V., et al. (1999). Human immunodeficiency virus type 1 integrase protein promotes reverse transcription through specific interactions with the nucleoprotein reverse transcription complex. J. Virol. 73, 2126-2135.
177. Wu, X., Liu, H., Xiao, H., Conway, J. A., Hunter, E., and Kappes, J. C. (1997). Functional RT and IN incorporated into HIV-1 particles independently of the gag/pol precursor protein. EMBO J. 16, 5113-5122. doi: 10.1093/emboj/16.16.5113.
178. Wu, X., Liu, H., Xiao, H., Kim, J., Seshaiah, P., Natsoulis, G., et al. (1995). Targeting foreign proteins to human immunodeficiency virus particles via fusion with Vpr and Vpx. J. Virol. 69, 3389-3398.
179. Yan, N., O'Day, E., Wheeler, L. A., Engelman, A., and Lieberman, J. (2011). HIV DNA is heavily uracilated, which protects it from autointegration. Proc. Natl. Acad. Sci. U.S.A. 108, 9244-9249. doi: 10.1073/pnas.1102943108.
180. Yang, B., Chen, K., Zhang, C., Huang, S., and Zhang, H. (2007). Virion-associated uracil DNA glycosylase-2 and apurinic/apyrimidinic endonuclease are involved in the degradation of APOBEC3G-edited nascent HIV-1 DNA. J. Biol. Chem. 282, 11667-11675. doi: 10.1074/jbc.M606864200.
181. Yao, X. J., Kobinger, G., Dandache, S., Rougeau, N., and Cohen, E. (1999). HIV-1 Vpr-chloramphenicol acetyltransferase fusion proteins: sequence requirement for virion incorporation and analysis of antiviral effect. Gene Ther. 6, 1590-1599. doi: 10.1038/sj.gt.3300988.
182. Yao, X.-J., Mouland, A. J., Subbramanian, R. A., Forget, J., Rougeau, N., Bergeron, D., et al. (1998). Vpr stimulates viral expression and induces cell killing in human immunodeficiency virus type 1-infected dividing jurkat T cells. J. Virol. 72, 4686-4693.
183. Zander, K., Sherman, M. P., Tessmer, U., Bruns, K., Wray, V., Prechtel, A. T., et al. (2003). Cyclophilin a interacts with HIV-1 Vpr and is required for its functional expression. J. Biol. Chem. 278, 43202-43213. doi: 10.1074/jbc.M305414200.
184. Zhang, S., Pointer, D., Singer, G., Feng, Y., Park, K., and Zhao, L. J. (1998). Direct binding to nucleic acids by Vpr of human immunodeficiency virus type 1. Gene 212, 157-166. doi: 10.1016/S0378-1119(98)00178-4.
185. Zhao, L. J., Wang, L., Mukherjee, S., and Narayan, O. (1994). Biochemical mechanism of HIV-1 Vpr function. oligomerization mediated by the N-terminal domain. J. Biol. Chem. 269, 32131-32137.
186. Zhou, Y., and Ratner, L. (2000). Phosphorylation of human immunodeficiency virus type 1 Vpr regulates cell cycle arrest. J. Virol. 74, 6520-6527. doi: 10.1128/JVI.74.14.6520-6527.2000.
187. Zhu, Y., Gelbard, H. A., Roshal, M., Pursell, S., Jamieson, B. D., and Planelles, V. (2001). Comparison of cell cycle arrest, transactivation, and apoptosis induced by the simian immunodeficiency virus SIVagm and human immunodeficiency virus type 1 vpr genes. J. Virol. 75, 3791-3801. doi: 10.1128/JVI.75.8.3791-3801.2001.
188. 2AX focus formation. Mol. Cell. Biol. 24, 9286-9294. doi: 10.1128/MCB.24.21.9286-9294.2004.