HIV-1 Accessory Protein Vpr: Relevance in the pathogenesis of HIV and potential for therapeutic intervention

Retrovirology

Volumn 8, Issue , 2011, Pages

  Kogan, Michael ^a   Rappaport, Jay ^a  

^a TEMPLE UNIVERSITY SCHOOL OF MEDICINE   (United States)

Author keywords

[No Author keywords available]

Indexed keywords

CELL PROTEIN; PROTEIN DCAF 1; UNCLASSIFIED DRUG; VPR PROTEIN; VPR PROTEIN, HUMAN IMMUNODEFICIENCY VIRUS 1;

ACQUIRED IMMUNE DEFICIENCY SYNDROME; BONE MARROW CELL; CD4+ T LYMPHOCYTE; CELL CYCLE ARREST; CELL DIFFERENTIATION; CELL PROLIFERATION; HUMAN; HUMAN IMMUNODEFICIENCY VIRUS 1; HUMAN IMMUNODEFICIENCY VIRUS INFECTION; LONG TERMINAL REPEAT; MACROPHAGE; NONHUMAN; PATHOGENESIS; PERSISTENT VIRUS INFECTION; PROTEIN BINDING; PROTEIN FUNCTION; PROTEIN TRANSPORT; REVIEW; VIRION; VIRUS DNA CELL DNA INTERACTION; ANIMAL; DRUG ANTAGONISM; GENETICS; HUMAN IMMUNODEFICIENCY VIRUS; IMMUNOLOGY; METABOLISM; PATHOGENICITY; VIROLOGY;

HUMAN IMMUNODEFICIENCY VIRUS 1;

ANIMALS; HIV; HIV INFECTIONS; HUMANS; VPR GENE PRODUCTS, HUMAN IMMUNODEFICIENCY VIRUS;

EID: 79953848334     PISSN: None     EISSN: 17424690     Source Type: Journal    
DOI: 10.1186/1742-4690-8-25     Document Type: Review

References (239)

1. Cohen EA, Terwilliger EF, Jalinoos Y, Proulx J, Sodroski JG, Haseltine WA. Identification of HIV-1 vpr product and function. J Acquir Immune Defic Syndr 1990, 3:11-18.
2. Yuan X, Matsuda Z, Matsuda M, Essex M, Lee TH. Human immunodeficiency virus vpr gene encodes a virion-associated protein. AIDS Res Hum Retroviruses 1990, 6:1265-1271.
3. Emerman M. HIV-1, Vpr and the cell cycle. Curr Biol 1996, 6:1096-1103. 10.1016/S0960-9822(02)00676-0, 8805364.
4. Planelles V, Jowett JB, Li QX, Xie Y, Hahn B, Chen IS. Vpr-induced cell cycle arrest is conserved among primate lentiviruses. J Virol 1996, 70:2516-2524. 190097, 8642681.
5. Tristem M, Marshall C, Karpas A, Hill F. Evolution of the primate lentiviruses: evidence from vpx and vpr. Embo J 1992, 11:3405-3412. 556875, 1324171.
6. Feldherr CM, Feldherr AB. The nuclear membrane as a barrier to the free diffusion of proteins. Nature 1960, 185:250-251. 10.1038/185250a0, 13822019.
7. Lewis PF, Emerman M. Passage through mitosis is required for oncoretroviruses but not for the human immunodeficiency virus. J Virol 1994, 68:510-516. 236313, 8254763.
8. Roe T, Reynolds TC, Yu G, Brown PO. Integration of murine leukemia virus DNA depends on mitosis. Embo J 1993, 12:2099-2108. 413431, 8491198.
9. Lewis P, Hensel M, Emerman M. Human immunodeficiency virus infection of cells arrested in the cell cycle. Embo J 1992, 11:3053-3058. 556788, 1322294.
10. Bukrinsky MI, Sharova N, Dempsey MP, Stanwick TL, Bukrinskaya AG, Haggerty S, Stevenson M. Active nuclear import of human immunodeficiency virus type 1 preintegration complexes. Proc Natl Acad Sci USA 1992, 89:6580-6584. 10.1073/pnas.89.14.6580, 49545, 1631159.
11. 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, 69:7909-7916. 189735, 7494303.
12. Lu YL, Spearman P, Ratner L. Human immunodeficiency virus type 1 viral protein R localization in infected cells and virions. J Virol 1993, 67:6542-6550. 238091, 8411357.
13. 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, 212:331-339. 10.1006/viro.1995.1490, 7571402.
14. Gallay P, Hope T, Chin D, Trono D. HIV-1 infection of nondividing cells through the recognition of integrase by the importin/karyopherin pathway. Proc Natl Acad Sci USA 1997, 94:9825-9830. 10.1073/pnas.94.18.9825, 23276, 9275210.
15. Arhel NJ, Souquere-Besse S, Munier S, Souque P, Guadagnini S, Rutherford S, Prevost MC, Allen TD, Charneau P. HIV-1 DNA Flap formation promotes uncoating of the pre-integration complex at the nuclear pore. EMBO J 2007, 26:3025-3037. 10.1038/sj.emboj.7601740, 1894778, 17557080.
16. 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, 80:3712-3720. 10.1128/JVI.80.8.3712-3720.2006, 1440469, 16571788.
17. Gorlich D. Nuclear protein import. Curr Opin Cell Biol 1997, 9:412-419. 10.1016/S0955-0674(97)80015-4, 9159081.
18. Herold A, Truant R, Wiegand H, Cullen BR. Determination of the functional domain organization of the importin alpha nuclear import factor. J Cell Biol 1998, 143:309-318. 10.1083/jcb.143.2.309, 2132842, 9786944.
19. Kobe B. Autoinhibition by an internal nuclear localization signal revealed by the crystal structure of mammalian importin alpha. Nat Struct Biol 1999, 6:388-397. 10.1038/7625, 10201409.
20. Moore MS, Blobel G. Purification of a Ran-interacting protein that is required for protein import into the nucleus. Proc Natl Acad Sci USA 1994, 91:10212-10216. 10.1073/pnas.91.21.10212, 44988, 7937864.
21. Moore MS, Blobel G. The GTP-binding protein Ran/TC4 is required for protein import into the nucleus. Nature 1993, 365:661-663. 10.1038/365661a0, 8413630.
22. Paschal BM, Gerace L. Identification of NTF2, a cytosolic factor for nuclear import that interacts with nuclear pore complex protein p62. J Cell Biol 1995, 129:925-937. 10.1083/jcb.129.4.925, 2120498, 7744965.
23. Melchior F, Paschal B, Evans J, Gerace L. Inhibition of nuclear protein import by nonhydrolyzable analogues of GTP and identification of the small GTPase Ran/TC4 as an essential transport factor. J Cell Biol 1993, 123:1649-1659. 10.1083/jcb.123.6.1649, 2290879, 8276887.
24. Melchior F, Guan T, Yokoyama N, Nishimoto T, Gerace L. GTP hydrolysis by Ran occurs at the nuclear pore complex in an early step of protein import. J Cell Biol 1995, 131:571-581. 10.1083/jcb.131.3.571, 2120626, 7593180.
25. Kotera I, Sekimoto T, Miyamoto Y, Saiwaki T, Nagoshi E, Sakagami H, Kondo H, Yoneda Y. Importin alpha transports CaMKIV to the nucleus without utilizing importin beta. Embo J 2005, 24:942-951. 10.1038/sj.emboj.7600587, 554133, 15719015.
26. Takizawa CG, Weis K, Morgan DO. Ran-independent nuclear import of cyclin B1-Cdc2 by importin beta. Proc Natl Acad Sci USA 1999, 96:7938-7943. 10.1073/pnas.96.14.7938, 22166, 10393926.
27. Aitchison JD, Blobel G, Rout MP. Kap104p: a karyopherin involved in the nuclear transport of messenger RNA binding proteins. Science 1996, 274:624-627. 10.1126/science.274.5287.624, 8849456.
28. Fridell RA, Truant R, Thorne L, Benson RE, Cullen BR. Nuclear import of hnRNP A1 is mediated by a novel cellular cofactor related to karyopherin-beta. J Cell Sci 1997, 110(Pt 11):1325-1331.
29. Michael WM, Choi M, Dreyfuss G. A nuclear export signal in hnRNP A1: a signal-mediated, temperature-dependent nuclear protein export pathway. Cell 1995, 83:415-422. 10.1016/0092-8674(95)90119-1, 8521471.
30. Pollard VW, Michael WM, Nakielny S, Siomi MC, Wang F, Dreyfuss G. A novel receptor-mediated nuclear protein import pathway. Cell 1996, 86:985-994. 10.1016/S0092-8674(00)80173-7, 8808633.
31. Siomi H, Dreyfuss G. A nuclear localization domain in the hnRNP A1 protein. J Cell Biol 1995, 129:551-560. 10.1083/jcb.129.3.551, 2120450, 7730395.
32. Nakielny S, Siomi MC, Siomi H, Michael WM, Pollard V, Dreyfuss G. Transportin: nuclear transport receptor of a novel nuclear protein import pathway. Exp Cell Res 1996, 229:261-266. 10.1006/excr.1996.0369, 8986607.
33. Palacios I, Weis K, Klebe C, Mattaj IW, Dingwall C. RAN/TC4 mutants identify a common requirement for snRNP and protein import into the nucleus. J Cell Biol 1996, 133:485-494. 10.1083/jcb.133.3.485, 2120818, 8636225.
34. Jenkins Y, McEntee M, Weis K, Greene WC. Characterization of HIV-1 vpr nuclear import: analysis of signals and pathways. J Cell Biol 1998, 143:875-885. 10.1083/jcb.143.4.875, 2132945, 9817747.
35. Efthymiadis A, Shao H, Hubner S, Jans DA. Kinetic characterization of the human retinoblastoma protein bipartite nuclear localization sequence (NLS) in vivo and in vitro. A comparison with the SV40 large T-antigen NLS. J Biol Chem 1997, 272:22134-22139. 10.1074/jbc.272.35.22134, 9268357.
36. Gorlich D, Henklein P, Laskey RA, Hartmann E. A 41 amino acid motif in importin-alpha confers binding to importin-beta and hence transit into the nucleus. Embo J 1996, 15:1810-1817. 450097, 8617226.
37. Jans DA, Jans P, Julich T, Briggs LJ, Xiao CY, Piller SC. Intranuclear binding by the HIV-1 regulatory protein VPR is dependent on cytosolic factors. Biochem Biophys Res Commun 2000, 270:1055-1062. 10.1006/bbrc.2000.2559, 10772949.
38. Nitahara-Kasahara Y, Kamata M, Yamamoto T, Zhang X, Miyamoto Y, Muneta K, Iijima S, Yoneda Y, Tsunetsugu-Yokota Y, Aida Y. Novel nuclear import of Vpr promoted by importin alpha is crucial for human immunodeficiency virus type 1 replication in macrophages. J Virol 2007, 81:5284-5293. 10.1128/JVI.01928-06, 1900242, 17344301.
39. Kamata M, Nitahara-Kasahara Y, Miyamoto Y, Yoneda Y, Aida Y. Importin-alpha promotes passage through the nuclear pore complex of human immunodeficiency virus type 1 Vpr. J Virol 2005, 79:3557-3564. 10.1128/JVI.79.6.3557-3564.2005, 1075686, 15731250.
40. Balliet JW, Kolson DL, Eiger G, Kim FM, McGann KA, Srinivasan A, Collman R. 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 1994, 200:623-631. 10.1006/viro.1994.1225, 8178448.
41. 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, 206:935-944. 10.1006/viro.1995.1016, 7531918.
42. Hattori N, Michaels F, Fargnoli K, Marcon L, Gallo RC, Franchini G. The human immunodeficiency virus type 2 vpr gene is essential for productive infection of human macrophages. Proc Natl Acad Sci USA 1990, 87:8080-8084. 10.1073/pnas.87.20.8080, 54896, 2236020.
43. Ogawa K, Shibata R, Kiyomasu T, Higuchi I, Kishida Y, Ishimoto A, Adachi A. Mutational analysis of the human immunodeficiency virus vpr open reading frame. J Virol 1989, 63:4110-4114. 251018, 2474678.
44. Blomer U, Naldini L, Kafri T, Trono D, Verma IM, Gage FH. Highly efficient and sustained gene transfer in adult neurons with a lentivirus vector. J Virol 1997, 71:6641-6649. 191942, 9261386.
45. Agostini I, Popov S, Hao T, Li JH, Dubrovsky L, Chaika O, Chaika N, Lewis R, Bukrinsky M. Phosphorylation of Vpr regulates HIV type 1 nuclear import and macrophage infection. AIDS Res Hum Retroviruses 2002, 18:283-288. 10.1089/088922202753472856, 11860675.
46. Caly L, Saksena NK, Piller SC, Jans DA. Impaired nuclear import and viral incorporation of Vpr derived from a HIV long-term non-progressor. Retrovirology 2008, 5:67. 10.1186/1742-4690-5-67, 2515335, 18638397.
47. 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, 72:6004-6013. 110405, 9621063.
48. 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, 70:1027-1032. 189908, 8551560.
49. Jacquot G, Le Rouzic E, David A, Mazzolini J, Bouchet J, Bouaziz S, Niedergang F, Pancino G, Benichou S. Localization of HIV-1 Vpr to the nuclear envelope: impact on Vpr functions and virus replication in macrophages. Retrovirology 2007, 4:84. 10.1186/1742-4690-4-84, 2211753, 18039376.
50. Vodicka MA, Koepp DM, Silver PA, Emerman M. HIV-1 Vpr interacts with the nuclear transport pathway to promote macrophage infection. Genes Dev 1998, 12:175-185. 10.1101/gad.12.2.175, 316441, 9436978.
51. 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, 273:13347-13352. 10.1074/jbc.273.21.13347, 9582382.
52. Keele BF, Giorgi EE, Salazar-Gonzalez JF, Decker JM, Pham KT, Salazar MG, Sun C, Grayson T, Wang S, Li H, et al. Identification and characterization of transmitted and early founder virus envelopes in primary HIV-1 infection. Proc Natl Acad Sci USA 2008, 105:7552-7557. 10.1073/pnas.0802203105, 2387184, 18490657.
53. Fischer W, Ganusov VV, Giorgi EE, Hraber PT, Keele BF, Leitner T, Han CS, Gleasner CD, Green L, Lo CC, et al. Transmission of single HIV-1 genomes and dynamics of early immune escape revealed by ultra-deep sequencing. PLoS One 2010, 5:e12303. 10.1371/journal.pone.0012303, 2924888, 20808830.
54. Iijima S, Nitahara-Kasahara Y, Kimata K, Zhong Zhuang W, Kamata M, Isogai M, Miwa M, Tsunetsugu-Yokota Y, Aida Y. Nuclear localization of Vpr is crucial for the efficient replication of HIV-1 in primary CD4+ T cells. Virology 2004, 327:249-261. 10.1016/j.virol.2004.06.024, 15351213.
55. Bukrinsky MI, Haffar OK. HIV-1 nuclear import: in search of a leader. Front Biosci 1997, 2:d578-587.
56. Yamashita M, Perez O, Hope TJ, Emerman M. Evidence for direct involvement of the capsid protein in HIV infection of nondividing cells. PLoS Pathog 2007, 3:1502-1510. 10.1371/journal.ppat.0030156, 2042020, 17967060.
57. Craigo JK, Montelaro RC. Lentivirus Tropism and Disease. Lentiviruses and Macrophages: Molecular and Cellular Interactions 2010, 1-24. Norfolk: Caister Academic Press, Desport M.
58. Morellet N, Bouaziz S, Petitjean P, Roques BP. NMR structure of the HIV-1 regulatory protein VPR. J Mol Biol 2003, 327:215-227. 10.1016/S0022-2836(03)00060-3, 12614620.
59. Mahalingam S, Ayyavoo V, Patel M, Kieber-Emmons T, Weiner DB. Nuclear import, virion incorporation, and cell cycle arrest/differentiation are mediated by distinct functional domains of human immunodeficiency virus type 1 Vpr. J Virol 1997, 71:6339-6347. 191907, 9261351.
60. Nie Z, Bergeron D, Subbramanian RA, Yao XJ, Checroune F, Rougeau N, Cohen EA. 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 1998, 72:4104-4115. 109640, 9557700.
61. Singh SP, Tomkowicz B, Lai D, Cartas M, Mahalingam S, Kalyanaraman VS, Murali R, Srinivasan A. Functional role of residues corresponding to helical domain II (amino acids 35 to 46) of human immunodeficiency virus type 1 Vpr. J Virol 2000, 74:10650-10657. 10.1128/JVI.74.22.10650-10657.2000, 110939, 11044109.
62. Yao XJ, Subbramanian RA, Rougeau N, Boisvert F, Bergeron D, Cohen EA. Mutagenic analysis of human immunodeficiency virus type 1 Vpr: role of a predicted N-terminal alpha-helical structure in Vpr nuclear localization and virion incorporation. J Virol 1995, 69:7032-7044. 189623, 7474123.
63. Fritz JV, Didier P, Clamme JP, Schaub E, Muriaux D, Cabanne C, Morellet N, Bouaziz S, Darlix JL, Mely Y, de Rocquigny H. Direct Vpr-Vpr interaction in cells monitored by two photon fluorescence correlation spectroscopy and fluorescence lifetime imaging. Retrovirology 2008, 5:87. 10.1186/1742-4690-5-87, 2562391, 18808682.
64. Agostini I, Popov S, Li J, Dubrovsky L, Hao T, Bukrinsky M. Heat-shock protein 70 can replace viral protein R of HIV-1 during nuclear import of the viral preintegration complex. Exp Cell Res 2000, 259:398-403. 10.1006/excr.2000.4992, 10964507.
65. Popov S, Rexach M, Zybarth G, Reiling N, Lee MA, Ratner L, Lane CM, Moore MS, Blobel G, Bukrinsky M. Viral protein R regulates nuclear import of the HIV-1 pre-integration complex. Embo J 1998, 17:909-917. 10.1093/emboj/17.4.909, 1170440, 9463369.
66. Kamata M, Aida Y. Two putative alpha-helical domains of human immunodeficiency virus type 1 Vpr mediate nuclear localization by at least two mechanisms. J Virol 2000, 74:7179-7186. 10.1128/JVI.74.15.7179-7186.2000, 112238, 10888660.
67. 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, 277:45091-45098. 10.1074/jbc.M207439200, 12228227.
68. Radu A, Moore MS, Blobel G. The peptide repeat domain of nucleoporin Nup98 functions as a docking site in transport across the nuclear pore complex. Cell 1995, 81:215-222. 10.1016/0092-8674(95)90331-3, 7736573.
69. Rexach M, Blobel G. Protein import into nuclei: association and dissociation reactions involving transport substrate, transport factors, and nucleoporins. Cell 1995, 83:683-692. 10.1016/0092-8674(95)90181-7, 8521485.
70. Kutay U, Izaurralde E, Bischoff FR, Mattaj IW, Gorlich D. Dominant-negative mutants of importin-beta block multiple pathways of import and export through the nuclear pore complex. Embo J 1997, 16:1153-1163. 10.1093/emboj/16.6.1153, 1169714, 9135132.
71. Karni O, Friedler A, Zakai N, Gilon C, Loyter A. A peptide derived from the N-terminal region of HIV-1 Vpr promotes nuclear import in permeabilized cells: elucidation of the NLS region of the Vpr. FEBS Lett 1998, 429:421-425. 10.1016/S0014-5793(98)00645-0, 9662462.
72. Zhou Y, Lu Y, Ratner L. Arginine residues in the C-terminus of HIV-1 Vpr are important for nuclear localization and cell cycle arrest. Virology 1998, 242:414-424. 10.1006/viro.1998.9028, 9514978.
73. Stewart SA, Poon B, Jowett JB, Chen IS. Human immunodeficiency virus type 1 Vpr induces apoptosis following cell cycle arrest. J Virol 1997, 71:5579-5592. 191800, 9188632.
74. Levy DN, Refaeli Y, MacGregor RR, Weiner DB. Serum Vpr regulates productive infection and latency of human immunodeficiency virus type 1. Proc Natl Acad Sci USA 1994, 91:10873-10877. 10.1073/pnas.91.23.10873, 45128, 7971975.
75. Levy DN, Refaeli Y, Weiner DB. Extracellular Vpr protein increases cellular permissiveness to human immunodeficiency virus replication and reactivates virus from latency. J Virol 1995, 69:1243-1252. 188697, 7815499.
76. Agostini I, Navarro JM, Rey F, Bouhamdan M, Spire B, Vigne R, Sire J. The human immunodeficiency virus type 1 Vpr transactivator: cooperation with promoter-bound activator domains and binding to TFIIB. J Mol Biol 1996, 261:599-606. 10.1006/jmbi.1996.0485, 8800208.
77. Cohen EA, Dehni G, Sodroski JG, Haseltine WA. Human immunodeficiency virus vpr product is a virion-associated regulatory protein. J Virol 1990, 64:3097-3099. 249501, 2139896.
78. Wang L, Mukherjee S, Jia F, Narayan O, Zhao LJ. 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 1995, 270:25564-25569. 10.1074/jbc.270.43.25564, 7592727.
79. Ghosh D. Glucocorticoid receptor-binding site in the human immunodeficiency virus long terminal repeat. J Virol 1992, 66:586-590. 238321, 1727502.
80. Katsanakis CD, Sekeris CE, Spandidos DA. The human immunodeficiency virus long terminal repeat contains sequences showing partial homology to glucocorticoid responsive elements. Anticancer Res 1991, 11:381-383.
81. McAllister JJ, Phillips D, Millhouse S, Conner J, Hogan T, Ross HL, Wigdahl B. Analysis of the HIV-1 LTR NF-kappaB-proximal Sp site III: evidence for cell type-specific gene regulation and viral replication. Virology 2000, 274:262-277. 10.1006/viro.2000.0476, 10964770.
82. Soudeyns H, Geleziunas R, Shyamala G, Hiscott J, Wainberg MA. Identification of a novel glucocorticoid response element within the genome of the human immunodeficiency virus type 1. Virology 1993, 194:758-768. 10.1006/viro.1993.1317, 7684876.
83. Verhoef K, Sanders RW, Fontaine V, Kitajima S, Berkhout B. Evolution of the human immunodeficiency virus type 1 long terminal repeat promoter by conversion of an NF-kappaB enhancer element into a GABP binding site. J Virol 1999, 73:1331-1340. 103957, 9882338.
84. Vanitharani R, Mahalingam S, Rafaeli Y, Singh SP, Srinivasan A, Weiner DB, Ayyavoo V. HIV-1 Vpr transactivates LTR-directed expression through sequences present within -278 to -176 and increases virus replication in vitro. Virology 2001, 289:334-342. 10.1006/viro.2001.1153, 11689055.
85. Felzien LK, Woffendin C, Hottiger MO, Subbramanian RA, Cohen EA, Nabel GJ. HIV transcriptional activation by the accessory protein, VPR, is mediated by the p300 co-activator. Proc Natl Acad Sci USA 1998, 95:5281-5286. 10.1073/pnas.95.9.5281, 20252, 9560267.
86. Kino T, Tsukamoto M, Chrousos G. Transcription factor TFIIH components enhance the GR coactivator activity but not the cell cycle-arresting activity of the human immunodeficiency virus type-1 protein Vpr. Biochem Biophys Res Commun 2002, 298:17-23. 10.1016/S0006-291X(02)02442-7, 12379213.
87. Sawaya BE, Khalili K, Rappaport J, Serio D, Chen W, Srinivasan A, Amini S. Suppression of HIV-1 transcription and replication by a Vpr mutant. Gene Ther 1999, 6:947-950. 10.1038/sj.gt.3300907, 10505122.
88. Sawaya BE, Khalili K, Gordon J, Taube R, Amini S. Cooperative interaction between HIV-1 regulatory proteins Tat and Vpr modulates transcription of the viral genome. J Biol Chem 2000, 275:35209-35214. 10.1074/jbc.M005197200, 10931842.
89. Refaeli Y, Levy DN, Weiner DB. The glucocorticoid receptor type II complex is a target of the HIV-1 vpr gene product. Proc Natl Acad Sci USA 1995, 92:3621-3625. 10.1073/pnas.92.8.3621, 42219, 7724608.
90. Kino T, Gragerov A, Kopp JB, Stauber RH, Pavlakis GN, Chrousos GP. The HIV-1 virion-associated protein vpr is a coactivator of the human glucocorticoid receptor. J Exp Med 1999, 189:51-62. 10.1084/jem.189.1.51, 1887689, 9874563.
91. Sherman MP, de Noronha CM, Pearce D, Greene WC. Human immunodeficiency virus type 1 Vpr contains two leucine-rich helices that mediate glucocorticoid receptor coactivation independently of its effects on G(2) cell cycle arrest. J Virol 2000, 74:8159-8165. 10.1128/JVI.74.17.8159-8165.2000, 112350, 10933727.
92. Kino T, Gragerov A, Slobodskaya O, Tsopanomichalou M, Chrousos GP, Pavlakis GN. Human immunodeficiency virus type 1 (HIV-1) accessory protein Vpr induces transcription of the HIV-1 and glucocorticoid-responsive promoters by binding directly to p300/CBP coactivators. J Virol 2002, 76:9724-9734. 10.1128/JVI.76.19.9724-9734.2002, 136530, 12208951.
93. Thotala D, Schafer EA, Tungaturthi PK, Majumder B, Janket ML, Wagner M, Srinivasan A, Watkins S, Ayyavoo V. Structure-functional analysis of human immunodeficiency virus type 1 (HIV-1) Vpr: role of leucine residues on Vpr-mediated transactivation and virus replication. Virology 2004, 328:89-100. 10.1016/j.virol.2004.07.013, 15380361.
94. Ramanathan MP, Curley E, Su M, Chambers JA, Weiner DB. Carboxyl terminus of hVIP/mov34 is critical for HIV-1-Vpr interaction and glucocorticoid-mediated signaling. J Biol Chem 2002, 277:47854-47860. 10.1074/jbc.M203905200, 12237292.
95. Muthumani K, Choo AY, Zong WX, Madesh M, Hwang DS, Premkumar A, Thieu KP, Emmanuel J, Kumar S, Thompson CB, Weiner DB. The HIV-1 Vpr and glucocorticoid receptor complex is a gain-of-function interaction that prevents the nuclear localization of PARP-1. Nat Cell Biol 2006, 8:170-179. 10.1038/ncb1352, 16429131.
96. Poli G, Kinter A, Justement JS, Kehrl JH, Bressler P, Stanley S, Fauci AS. Tumor necrosis factor alpha functions in an autocrine manner in the induction of human immunodeficiency virus expression. Proc Natl Acad Sci USA 1990, 87:782-785. 10.1073/pnas.87.2.782, 53350, 2300561.
97. Lenardo MJ, Baltimore D. NF-kappa B: a pleiotropic mediator of inducible and tissue-specific gene control. Cell 1989, 58:227-229. 10.1016/0092-8674(89)90833-7, 2665943.
98. Chang HK, Gallo RC, Ensoli B. Regulation of Cellular Gene Expression and Function by the Human Immunodeficiency Virus Type 1 Tat Protein. J Biomed Sci 1995, 2:189-202. 10.1007/BF02253380, 11725056.
99. Chatterton RT, Green D, Harris S, Grossman A, Hechter O. Longitudinal study of adrenal steroids in a cohort of HIV-infected patients with hemophilia. J Lab Clin Med 1996, 127:545-552. 10.1016/S0022-2143(96)90145-6, 8648259.
100. Kawa SK, Thompson EB. Lymphoid cell resistance to glucocorticoids in HIV infection. J Steroid Biochem Mol Biol 1996, 57:259-263. 10.1016/0960-0760(96)00001-5, 8639461.
101. Lortholary O, Christeff N, Casassus P, Thobie N, Veyssier P, Trogoff B, Torri O, Brauner M, Nunez EA, Guillevin L. Hypothalamo-pituitary-adrenal function in human immunodeficiency virus-infected men. J Clin Endocrinol Metab 1996, 81:791-796. 10.1210/jc.81.2.791, 8636305.
102. Laudat A, Blum L, Guechot J, Picard O, Cabane J, Imbert JC, Giboudeau J. Changes in systemic gonadal and adrenal steroids in asymptomatic human immunodeficiency virus-infected men: relationship with the CD4 cell counts. Eur J Endocrinol 1995, 133:418-424. 10.1530/eje.0.1330418, 7581964.
103. Biglino A, Limone P, Forno B, Pollono A, Cariti G, Molinatti GM, Gioannini P. Altered adrenocorticotropin and cortisol response to corticotropin-releasing hormone in HIV-1 infection. Eur J Endocrinol 1995, 133:173-179. 10.1530/eje.0.1330173, 7655641.
104. Kumar M, Kumar AM, Morgan R, Szapocznik J, Eisdorfer C. Abnormal pituitary-adrenocortical response in early HIV-1 infection. J Acquir Immune Defic Syndr 1993, 6:61-65.
105. Kino T, Kopp JB, Chrousos GP. Glucocorticoids suppress human immunodeficiency virus type-1 long terminal repeat activity in a cell type-specific, glucocorticoid receptor-mediated fashion: direct protective effects at variance with clinical phenomenology. J Steroid Biochem Mol Biol 2000, 75:283-290. 10.1016/S0960-0760(00)00187-4, 11282284.
106. Laurence J, Sellers MB, Sikder SK. Effect of glucocorticoids on chronic human immunodeficiency virus (HIV) infection and HIV promoter-mediated transcription. Blood 1989, 74:291-297.
107. Mitra D, Sikder S, Laurence J. Inhibition of tat-activated, HIV-1 long terminal repeat-mediated gene expression by glucocorticoids. AIDS Res Hum Retroviruses 1993, 9:1055-1056. 10.1089/aid.1993.9.1055, 8312048.
108. Mitra D, Sikder SK, Laurence J. Role of glucocorticoid receptor binding sites in the human immunodeficiency virus type 1 long terminal repeat in steroid-mediated suppression of HIV gene expression. Virology 1995, 214:512-521. 10.1006/viro.1995.0062, 8553553.
109. Russo FO, Patel PC, Ventura AM, Pereira CA. HIV-1 long terminal repeat modulation by glucocorticoids in monocytic and lymphocytic cell lines. Virus Res 1999, 64:87-94. 10.1016/S0168-1702(99)00082-9, 10500286.
110. Furth PA, Westphal H, Hennighausen L. Expression from the HIV-LTR is stimulated by glucocorticoids and pregnancy. AIDS Res Hum Retroviruses 1990, 6:553-560. 10.1089/aid.1990.6.553, 2340206.
111. Kinter AL, Biswas P, Alfano M, Justement JS, Mantelli B, Rizzi C, Gatti AR, Vicenzi E, Bressler P, Poli G. Interleukin-6 and glucocorticoids synergistically induce human immunodeficiency virus type-1 expression in chronically infected U1 cells by a long terminal repeat independent post-transcriptional mechanism. Mol Med 2001, 7:668-678. 1949996, 11713366.
112. Hoshino S, Konishi M, Mori M, Shimura M, Nishitani C, Kuroki Y, Koyanagi Y, Kano S, Itabe H, Ishizaka Y. HIV-1 Vpr induces TLR4/MyD88-mediated IL-6 production and reactivates viral production from latency. J Leukoc Biol 2010, 87:1133-1143. 10.1189/jlb.0809547, 20145198.
113. Bressler P, Poli G, Justement JS, Biswas P, Fauci AS. Glucocorticoids synergize with tumor necrosis factor alpha in the induction of HIV expression from a chronically infected promonocytic cell line. AIDS Res Hum Retroviruses 1993, 9:547-551. 10.1089/aid.1993.9.547, 8347399.
114. Capitanio JP, Mendoza SP, Lerche NW, Mason WA. Social stress results in altered glucocorticoid regulation and shorter survival in simian acquired immune deficiency syndrome. Proc Natl Acad Sci USA 1998, 95:4714-4719. 10.1073/pnas.95.8.4714, 22556, 9539804.
115. Corley PA. Induction of interleukin-1 and glucocorticoid hormones by HIV promotes viral replication and links human chromosome 2 to AIDS pathogenesis: genetic mechanisms and therapeutic implications. Med Hypotheses 1997, 48:415-421. 10.1016/S0306-9877(97)90040-2, 9185130.
116. Nair MP, Saravolatz LD, Schwartz SA. Selective inhibitory effects of stress hormones on natural killer (NK) cell activity of lymphocytes from AIDS patients. Immunol Invest 1995, 24:689-699. 10.3109/08820139509060698, 8543334.
117. Schafer EA, Venkatachari NJ, Ayyavoo V. Antiviral effects of mifepristone on human immunodeficiency virus type-1 (HIV-1): targeting Vpr and its cellular partner, the glucocorticoid receptor (GR). Antiviral Res 2006, 72:224-232. 10.1016/j.antiviral.2006.06.008, 16889838.
118. Wiegers K, Schwarck D, Reimer R, Bohn W. Activation of the glucocorticoid receptor releases unstimulated PBMCs from an early block in HIV-1 replication. Virology 2008, 375:73-84. 10.1016/j.virol.2008.01.037, 18295813.
119. 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, 15:6155-6165. 452436, 8947037.
120. 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, 69:2378-2383. 188910, 7884883.
121. Subbramanian RA, Kessous-Elbaz A, Lodge R, Forget J, Yao XJ, Bergeron D, Cohen EA. Human immunodeficiency virus type 1 Vpr is a positive regulator of viral transcription and infectivity in primary human macrophages. J Exp Med 1998, 187:1103-1111. 10.1084/jem.187.7.1103, 2212198, 9529326.
122. Belzile JP, Duisit G, Rougeau N, Mercier J, Finzi A, Cohen EA. HIV-1 Vpr-mediated G2 arrest involves the DDB1-CUL4AVPRBP E3 ubiquitin ligase. PLoS Pathog 2007, 3:e85. 10.1371/journal.ppat.0030085, 1914068, 17630831.
123. DeHart JL, Zimmerman ES, Ardon O, Monteiro-Filho CM, Arganaraz ER, Planelles V. HIV-1 Vpr activates the G2 checkpoint through manipulation of the ubiquitin proteasome system. Virol J 2007, 4:57. 10.1186/1743-422X-4-57, 1904188, 17559673.
124. Hrecka K, Gierszewska M, Srivastava S, Kozaczkiewicz L, Swanson SK, Florens L, Washburn MP, Skowronski J. Lentiviral Vpr usurps Cul4-DDB1[VprBP] E3 ubiquitin ligase to modulate cell cycle. Proc Natl Acad Sci USA 2007, 104:11778-11783. 10.1073/pnas.0702102104, 1906728, 17609381.
125. Le Rouzic E, Belaïdouni N, Estrabaud E, Morel M, Rain J, Transy C, Margottin-Goguet F. HIV1 Vpr arrests the cell cycle by recruiting DCAF1/VprBP, a receptor of the Cul4-DDB1 ubiquitin ligase. Cell Cycle 2007, 6:182-188. 10.4161/cc.6.2.3732, 17314515.
126. Schrofelbauer B, Hakata Y, Landau NR. HIV-1 Vpr function is mediated by interaction with the damage-specific DNA-binding protein DDB1. Proc Natl Acad Sci USA 2007, 104:4130-4135. 10.1073/pnas.0610167104, 1820720, 17360488.
127. Tan L, Ehrlich E, Yu XF. DDB1 and Cul4A are required for human immunodeficiency virus type 1 Vpr-induced G2 arrest. J Virol 2007, 81:10822-10830. 10.1128/JVI.01380-07, 2045451, 17626091.
128. Wen X, Duus KM, Friedrich TD, de Noronha CM. 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 2007, 282:27046-27057. 10.1074/jbc.M703955200, 17620334.
129. Zhao LJ, Mukherjee S, Narayan O. Biochemical mechanism of HIV-I Vpr function. Specific interaction with a cellular protein. J Biol Chem 1994, 269:15577-15582.
130. Ayinde D, Maudet C, Transy C, Margottin-Goguet F. Limelight on two HIV/SIV accessory proteins in macrophage infection: is Vpx overshadowing Vpr?. Retrovirology 2010, 7:35. 10.1186/1742-4690-7-35, 2867959, 20380700.
131. Casey L, Wen X, de Noronha CM. The functions of the HIV1 protein Vpr and its action through the DCAF1.DDB1.Cullin4 ubiquitin ligase. Cytokine 2010, 51:1-9. 10.1016/j.cyto.2010.02.018, 20347598.
132. Zimmerman E, Sherman M, Blackett J, Neidleman J, Kreis C, Mundt P, Williams S, Warmerdam M, Kahn J, Hecht F, et al. Human immunodeficiency virus type 1 Vpr induces DNA replication stress in vitro and in vivo. J Virol 2006, 80:10407-10418. 10.1128/JVI.01212-06, 1641771, 16956949.
133. Forget J, Yao XJ, Mercier J, Cohen EA. Human immunodeficiency virus type 1 vpr protein transactivation function: mechanism and identification of domains involved. J Mol Biol 1998, 284:915-923. 10.1006/jmbi.1998.2206, 9837715.
134. Goh WC, Rogel ME, Kinsey CM, Michael SF, Fultz PN, Nowak MA, Hahn BH, Emerman M. HIV-1 Vpr increases viral expression by manipulation of the cell cycle: a mechanism for selection of Vpr in vivo. Nat Med 1998, 4:65-71. 10.1038/nm0198-065, 9427608.
135. Igarashi T, Brown CR, Endo Y, Buckler-White A, Plishka R, Bischofberger N, Hirsch V, Martin MA. Macrophage are the principal reservoir and sustain high virus loads in rhesus macaques after the depletion of CD4+ T cells by a highly pathogenic simian immunodeficiency virus/HIV type 1 chimera (SHIV): Implications for HIV-1 infections of humans. Proc Natl Acad Sci USA 2001, 98:658-663. 10.1073/pnas.021551798, 14644, 11136236.
136. Tristem M, Marshall C, Karpas A, Petrik J, Hill F. Origin of vpx in lentiviruses. Nature 1990, 347:341-342. 10.1038/347341b0, 2145513.
137. Sharova N, Wu Y, Zhu X, Stranska R, Kaushik R, Sharkey M, Stevenson M. Primate lentiviral Vpx commandeers DDB1 to counteract a macrophage restriction. PLoS Pathog 2008, 4:e1000057. 10.1371/journal.ppat.1000057, 2323106, 18451984.
138. Srivastava S, Swanson SK, Manel N, Florens L, Washburn MP, Skowronski J. Lentiviral Vpx accessory factor targets VprBP/DCAF1 substrate adaptor for cullin 4 E3 ubiquitin ligase to enable macrophage infection. PLoS Pathog 2008, 4:e1000059. 10.1371/journal.ppat.1000059, 2330158, 18464893.
139. Bergamaschi A, Ayinde D, David A, Le Rouzic E, Morel M, Collin G, Descamps D, Damond F, Brun-Vezinet F, Nisole S, et al. The human immunodeficiency virus type 2 Vpx protein usurps the CUL4A-DDB1 DCAF1 ubiquitin ligase to overcome a postentry block in macrophage infection. J Virol 2009, 83:4854-4860. 10.1128/JVI.00187-09, 2682070, 19264781.
140. Zufferey R, Nagy D, Mandel RJ, Naldini L, Trono D. Multiply attenuated lentiviral vector achieves efficient gene delivery in vivo. Nat Biotechnol 1997, 15:871-875. 10.1038/nbt0997-871, 9306402.
141. Cosenza MA, Zhao ML, Lee SC. HIV-1 expression protects macrophages and microglia from apoptotic death. Neuropathol Appl Neurobiol 2004, 30:478-490. 10.1111/j.1365-2990.2004.00563.x, 15488024.
142. Fernandez Larrosa PN, Croci DO, Riva DA, Bibini M, Luzzi R, Saracco M, Mersich SE, Rabinovich GA, Peralta LM. Apoptosis resistance in HIV-1 persistently-infected cells is independent of active viral replication and involves modulation of the apoptotic mitochondrial pathway. Retrovirology 2008, 5:19. 10.1186/1742-4690-5-19, 2276517, 18261236.
143. Fukumori T, Akari H, Yoshida A, Fujita M, Koyama AH, Kagawa S, Adachi A. Regulation of cell cycle and apoptosis by human immunodeficiency virus type 1 Vpr. Microbes Infect 2000, 2:1011-1017. 10.1016/S1286-4579(00)01255-7, 10967282.
144. Yao XJ, Mouland AJ, Subbramanian RA, Forget J, Rougeau N, Bergeron D, Cohen EA. Vpr stimulates viral expression and induces cell killing in human immunodeficiency virus type 1-infected dividing Jurkat T cells. J Virol 1998, 72:4686-4693. 109992, 9573232.
145. Conti L, Rainaldi G, Matarrese P, Varano B, Rivabene R, Columba S, Sato A, Belardelli F, Malorni W, Gessani S. The HIV-1 vpr protein acts as a negative regulator of apoptosis in a human lymphoblastoid T cell line: possible implications for the pathogenesis of AIDS. J Exp Med 1998, 187:403-413. 10.1084/jem.187.3.403, 2212119, 9449720.
146. Rostad SW, Sumi SM, Shaw CM, Olson K, McDougall JK. Human immunodeficiency virus (HIV) infection in brains with AIDS-related leukoencephalopathy. AIDS Res Hum Retroviruses 1987, 3:363-373. 10.1089/aid.1987.3.363, 3447627.
147. McArthur JC. HIV dementia: an evolving disease. J Neuroimmunol 2004, 157:3-10. 10.1016/j.jneuroim.2004.08.042, 15579274.
148. Kure K, Llena JF, Lyman WD, Soeiro R, Weidenheim KM, Hirano A, Dickson DW. Human immunodeficiency virus-1 infection of the nervous system: an autopsy study of 268 adult, pediatric, and fetal brains. Hum Pathol 1991, 22:700-710. 10.1016/0046-8177(91)90293-X, 2071114.
149. Porwit A, Parravicini C, Petren AL, Barkhem T, Costanzi G, Josephs S, Biberfeld P. Cell association of HIV in AIDS-related encephalopathy and dementia. Apmis 1989, 97:79-90. 10.1111/j.1699-0463.1989.tb00759.x, 2914109.
150. Pumarola-Sune T, Navia BA, Cordon-Cardo C, Cho ES, Price RW. HIV antigen in the brains of patients with the AIDS dementia complex. Ann Neurol 1987, 21:490-496. 10.1002/ana.410210513, 3296948.
151. Williams KC, Corey S, Westmoreland SV, Pauley D, Knight H, deBakker C, Alvarez X, Lackner AA. Perivascular macrophages are the primary cell type productively infected by simian immunodeficiency virus in the brains of macaques: implications for the neuropathogenesis of AIDS. J Exp Med 2001, 193:905-915. 10.1084/jem.193.8.905, 2193403, 11304551.
152. Glass JD, Fedor H, Wesselingh SL, McArthur JC. Immunocytochemical quantitation of human immunodeficiency virus in the brain: correlations with dementia. Ann Neurol 1995, 38:755-762. 10.1002/ana.410380510, 7486867.
153. Fischer-Smith T, Tedaldi EM, Rappaport J. CD163/CD16 coexpression by circulating monocytes/macrophages in HIV: potential biomarkers for HIV infection and AIDS progression. AIDS Res Hum Retroviruses 2008, 24:417-421. 10.1089/aid.2007.0193, 18373432.
154. Pulliam L, Gascon R, Stubblebine M, McGuire D, McGrath MS. Unique monocyte subset in patients with AIDS dementia. Lancet 1997, 349:692-695. 10.1016/S0140-6736(96)10178-1, 9078201.
155. Fischer-Smith T, Croul S, Sverstiuk AE, Capini C, L'Heureux D, Regulier EG, Richardson MW, Amini S, Morgello S, Khalili K, Rappaport J. CNS invasion by CD14+/CD16+ peripheral blood-derived monocytes in HIV dementia: perivascular accumulation and reservoir of HIV infection. J Neurovirol 2001, 7:528-541. 10.1080/135502801753248114, 11704885.
156. Achim CL, Heyes MP, Wiley CA. Quantitation of human immunodeficiency virus, immune activation factors, and quinolinic acid in AIDS brains. J Clin Invest 1993, 91:2769-2775. 10.1172/JCI116518, 443343, 8514884.
157. Fischer-Smith T, Croul S, Adeniyi A, Rybicka K, Morgello S, Khalili K, Rappaport J. Macrophage/microglial accumulation and proliferating cell nuclear antigen expression in the central nervous system in human immunodeficiency virus encephalopathy. Am J Pathol 2004, 164:2089-2099. 10.1016/S0002-9440(10)63767-4, 1615769, 15161643.
158. Fischer-Smith T, Rappaport J. Evolving paradigms in the pathogenesis of HIV-1-associated dementia. Expert Rev Mol Med 2005, 7:1-26. 10.1017/S1462399405010239, 16321172.
159. Wheeler ED, Achim CL, Ayyavoo V. Immunodetection of human immunodeficiency virus type 1 (HIV-1) Vpr in brain tissue of HIV-1 encephalitic patients. J Neurovirol 2006, 12:200-210. 10.1080/13550280600827377, 16877301.
160. Piller SC, Jans P, Gage PW, Jans DA. Extracellular HIV-1 virus protein R causes a large inward current and cell death in cultured hippocampal neurons: implications for AIDS pathology. Proc Natl Acad Sci USA 1998, 95:4595-4600. 10.1073/pnas.95.8.4595, 22535, 9539783.
161. Jones GJ, Barsby NL, Cohen EA, Holden J, Harris K, Dickie P, Jhamandas J, Power C. HIV-1 Vpr causes neuronal apoptosis and in vivo neurodegeneration. J Neurosci 2007, 27:3703-3711. 10.1523/JNEUROSCI.5522-06.2007, 17409234.
162. Sabbah EN, Roques BP. Critical implication of the (70-96) domain of human immunodeficiency virus type 1 Vpr protein in apoptosis of primary rat cortical and striatal neurons. J Neurovirol 2005, 11:489-502. 10.1080/13550280500384941, 16338743.
163. Patel CA, Mukhtar M, Pomerantz RJ. Human immunodeficiency virus type 1 Vpr induces apoptosis in human neuronal cells. J Virol 2000, 74:9717-9726. 10.1128/JVI.74.20.9717-9726.2000, 112404, 11000244.
164. Brenneman DE, Westbrook GL, Fitzgerald SP, Ennist DL, Elkins KL, Ruff MR, Pert CB. Neuronal cell killing by the envelope protein of HIV and its prevention by vasoactive intestinal peptide. Nature 1988, 335:639-642. 10.1038/335639a0, 2845276.
165. Venkatesh LK, Arens MQ, Subramanian T, Chinnadurai G. Selective induction of toxicity to human cells expressing human immunodeficiency virus type 1 Tat by a conditionally cytotoxic adenovirus vector. Proc Natl Acad Sci USA 1990, 87:8746-8750. 10.1073/pnas.87.22.8746, 55036, 2247444.
166. Patel CA, Mukhtar M, Harley S, Kulkosky J, Pomerantz RJ. Lentiviral expression of HIV-1 Vpr induces apoptosis in human neurons. J Neurovirol 2002, 8:86-99. 10.1080/13550280290049552, 11935461.
167. Acheampong E, Mukhtar M, Parveen Z, Ngoubilly N, Ahmad N, Patel C, Pomerantz RJ. Ethanol strongly potentiates apoptosis induced by HIV-1 proteins in primary human brain microvascular endothelial cells. Virology 2002, 304:222-234. 10.1006/viro.2002.1666, 12504564.
168. Rom I, Deshmane SL, Mukerjee R, Khalili K, Amini S, Sawaya BE. HIV-1 Vpr deregulates calcium secretion in neural cells. Brain Res 2009, 2692350, 19328187.
169. D'Antoni S, Berretta A, Bonaccorso CM, Bruno V, Aronica E, Nicoletti F, Catania MV. Metabotropic glutamate receptors in glial cells. Neurochem Res 2008, 33:2436-2443.
170. Kitayama H, Miura Y, Ando Y, Hoshino S, Ishizaka Y, Koyanagi Y. Human immunodeficiency virus type 1 Vpr inhibits axonal outgrowth through induction of mitochondrial dysfunction. J Virol 2008, 82:2528-2542. 10.1128/JVI.02094-07, 2258941, 18094160.
171. Hogan TH, Nonnemacher MR, Krebs FC, Henderson A, Wigdahl B. HIV-1 Vpr binding to HIV-1 LTR C/EBP cis-acting elements and adjacent regions is sequence-specific. Biomed Pharmacother 2003, 57:41-48. 10.1016/S0753-3322(02)00333-5, 12642036.
172. Burdo TH, Nonnemacher M, Irish BP, Choi CH, Krebs FC, Gartner S, Wigdahl B. High-affinity interaction between HIV-1 Vpr and specific sequences that span the C/EBP and adjacent NF-kappaB sites within the HIV-1 LTR correlate with HIV-1-associated dementia. DNA Cell Biol 2004, 23:261-269. 10.1089/104454904773819842, 15142383.
173. Kilareski EM, Shah S, Nonnemacher MR, Wigdahl B. Regulation of HIV-1 transcription in cells of the monocyte-macrophage lineage. Retrovirology 2009, 6:118. 10.1186/1742-4690-6-118, 2805609, 20030845.
174. Si Q, Kim MO, Zhao ML, Landau NR, Goldstein H, Lee S. Vpr- and Nef-dependent induction of RANTES/CCL5 in microglial cells. Virology 2002, 301:342-353. 10.1006/viro.2002.1613, 12359436.
175. Wyatt CM, Rosenstiel PE, Klotman PE. HIV-associated nephropathy. Contrib Nephrol 2008, 159:151-161. full_text, 18391591.
176. Kopp J, Smith M, Nelson G, Johnson R, Freedman B, Bowden D, Oleksyk T, McKenzie L, Kajiyama H, Ahuja T, et al. MYH9 is a major-effect risk gene for focal segmental glomerulosclerosis. Nat Genet 2008, 40:1175-1184. 10.1038/ng.226, 2827354, 18794856.
177. Tang P, Jerebtsova M, Przygodzki R, Ray PE. Fibroblast growth factor-2 increases the renal recruitment and attachment of HIV-infected mononuclear cells to renal tubular epithelial cells. Pediatr Nephrol 2005, 20:1708-1716. 10.1007/s00467-005-2018-2, 16133048.
178. Dickie P, Roberts A, Uwiera R, Witmer J, Sharma K, Kopp JB. Focal glomerulosclerosis in proviral and c-fms transgenic mice links Vpr expression to HIV-associated nephropathy. Virology 2004, 322:69-81. 10.1016/j.virol.2004.01.026, 15063118.
179. Zhong J, Zuo Y, Ma J, Fogo AB, Jolicoeur P, Ichikawa I, Matsusaka T. Expression of HIV-1 genes in podocytes alone can lead to the full spectrum of HIV-1-associated nephropathy. Kidney Int 2005, 68:1048-1060. 10.1111/j.1523-1755.2005.00497.x, 16105035.
180. Zuo Y, Matsusaka T, Zhong J, Ma J, Ma LJ, Hanna Z, Jolicoeur P, Fogo AB, Ichikawa I. HIV-1 genes vpr and nef synergistically damage podocytes, leading to glomerulosclerosis. J Am Soc Nephrol 2006, 17:2832-2843. 10.1681/ASN.2005080878, 16988066.
181. Rosenstiel PE, Gruosso T, Letourneau AM, Chan JJ, LeBlanc A, Husain M, Najfeld V, Planelles V, D'Agati VD, Klotman ME, Klotman PE. HIV-1 Vpr inhibits cytokinesis in human proximal tubule cells. Kidney Int 2008, 74:1049-1058. 10.1038/ki.2008.303, 18614999.
182. Hiramatsu N, Hiromura K, Shigehara T, Kuroiwa T, Ideura H, Sakurai N, Takeuchi S, Tomioka M, Ikeuchi H, Kaneko Y, et al. Angiotensin II type 1 receptor blockade inhibits the development and progression of HIV-associated nephropathy in a mouse model. J Am Soc Nephrol 2007, 18:515-527. 10.1681/ASN.2006030217, 17229913.
183. Ayyavoo V, Muthumani K, Kudchodkar S, Zhang D, Ramanathan P, Dayes NS, Kim JJ, Sin JI, Montaner LJ, Weiner DB. HIV-1 viral protein R compromises cellular immune function in vivo. Int Immunol 2002, 14:13-22. 10.1093/intimm/14.1.13, 11751747.
184. Muthumani K, Bagarazzi M, Conway D, Hwang DS, Ayyavoo V, Zhang D, Manson K, Kim J, Boyer J, Weiner DB. Inclusion of Vpr accessory gene in a plasmid vaccine cocktail markedly reduces Nef vaccine effectiveness in vivo resulting in CD4 cell loss and increased viral loads in rhesus macaques. J Med Primatol 2002, 31:179-185. 10.1034/j.1600-0684.2002.02004.x, 12390540.
185. Bouzar AB, Villet S, Morin T, Rea A, Genestier L, Guiguen F, Garnier C, Mornex JF, Narayan O, Chebloune Y. Simian immunodeficiency virus Vpr/Vpx proteins kill bystander noninfected CD4+ T-lymphocytes by induction of apoptosis. Virology 2004, 326:47-56. 10.1016/j.virol.2004.05.016, 15262494.
186. Moon HS, Yang JS. Role of HIV Vpr as a regulator of apoptosis and an effector on bystander cells. Mol Cells 2006, 21:7-20.
187. Azad AA. Could Nef and Vpr proteins contribute to disease progression by promoting depletion of bystander cells and prolonged survival of HIV-infected cells?. Biochem Biophys Res Commun 2000, 267:677-685. 10.1006/bbrc.1999.1708, 10673351.
188. Groux H, Torpier G, Monte D, Mouton Y, Capron A, Ameisen JC. Activation-induced death by apoptosis in CD4+ T cells from human immunodeficiency virus-infected asymptomatic individuals. J Exp Med 1992, 175:331-340. 10.1084/jem.175.2.331, 2119133, 1346269.
189. Meyaard L, Schuitemaker H, Miedema F. T-cell dysfunction in HIV infection: anergy due to defective antigen-presenting cell function?. Immunol Today 1993, 14:161-164. 10.1016/0167-5699(93)90279-T, 8098942.
190. Yasuda J, Miyao T, Kamata M, Aida Y, Iwakura Y. T cell apoptosis causes peripheral T cell depletion in mice transgenic for the HIV-1 vpr gene. Virology 2001, 285:181-192. 10.1006/viro.2001.0964, 11437653.
191. Nishizawa M, Kamata M, Mojin T, Nakai Y, Aida Y. Induction of apoptosis by the Vpr protein of human immunodeficiency virus type 1 occurs independently of G(2) arrest of the cell cycle. Virology 2000, 276:16-26. 10.1006/viro.2000.0534, 11021990.
192. Li G, Park HU, Liang D, Zhao RY. Cell cycle G2/M arrest through an S phase-dependent mechanism by HIV-1 viral protein R. Retrovirology 2010, 7:59. 10.1186/1742-4690-7-59, 2909154, 20609246.
193. Muthumani K, Zhang D, Hwang DS, Kudchodkar S, Dayes NS, Desai BM, Malik AS, Yang JS, Chattergoon MA, Maguire HC, Weiner DB. Adenovirus encoding HIV-1 Vpr activates caspase 9 and induces apoptotic cell death in both p53 positive and negative human tumor cell lines. Oncogene 2002, 21:4613-4625. 10.1038/sj.onc.1205549, 12096338.
194. Shostak LD, Ludlow J, Fisk J, Pursell S, Rimel BJ, Nguyen D, Rosenblatt JD, Planelles V. Roles of p53 and caspases in the induction of cell cycle arrest and apoptosis by HIV-1 vpr. Exp Cell Res 1999, 251:156-165. 10.1006/excr.1999.4568, 10438581.
195. Stewart SA, Poon B, Song JY, Chen IS. Human immunodeficiency virus type 1 vpr induces apoptosis through caspase activation. J Virol 2000, 74:3105-3111. 10.1128/JVI.74.7.3105-3111.2000, 111809, 10708425.
196. Majumder B, Venkatachari NJ, Schafer EA, Janket ML, Ayyavoo V. 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 2007, 81:7388-7399. 10.1128/JVI.00893-06, 1933341, 17475642.
197. Richard J, Sindhu S, Pham TN, Belzile JP, Cohen EA. HIV-1 Vpr up-regulates expression of ligands for the activating NKG2D receptor and promotes NK cell-mediated killing. Blood 2010, 115:1354-1363. 10.1182/blood-2009-08-237370, 20008788.
198. Ward J, Davis Z, DeHart J, Zimmerman E, Bosque A, Brunetta E, Mavilio D, Planelles V, Barker E. HIV-1 Vpr triggers natural killer cell-mediated lysis of infected cells through activation of the ATR-mediated DNA damage response. PLoS Pathog 2009, 5:e1000613. 10.1371/journal.ppat.1000613, 2747015, 19798433.
199. Hong HS, Bhatnagar N, Ballmaier M, Schubert U, Henklein P, Volgmann T, Heiken H, Schmidt RE, Meyer-Olson D. Exogenous HIV-1 Vpr disrupts IFN-alpha response by plasmacytoid dendritic cells (pDCs) and subsequent pDC/NK interplay. Immunol Lett 2009, 125:100-104. 10.1016/j.imlet.2009.06.008, 19559726.
200. Majumder B, Venkatachari NJ, O'Leary S, Ayyavoo V. Infection with Vpr-positive human immunodeficiency virus type 1 impairs NK cell function indirectly through cytokine dysregulation of infected target cells. J Virol 2008, 82:7189-7200. 10.1128/JVI.01979-07, 2446960, 18417583.
201. Majumder B, Janket ML, Schafer EA, Schaubert K, Huang XL, Kan-Mitchell J, Rinaldo CR, Ayyavoo V. Human immunodeficiency virus type 1 Vpr impairs dendritic cell maturation and T-cell activation: implications for viral immune escape. J Virol 2005, 79:7990-8003. 10.1128/JVI.79.13.7990-8003.2005, 1143734, 15956545.
202. Mariani R, Rasala BA, Rutter G, Wiegers K, Brandt SM, Krausslich HG, Landau NR. Mouse-human heterokaryons support efficient human immunodeficiency virus type 1 assembly. J Virol 2001, 75:3141-3151. 10.1128/JVI.75.7.3141-3151.2001, 114108, 11238841.
203. Muthumani K, Desai BM, Hwang DS, Choo AY, Laddy DJ, Thieu KP, Rao RG, Weiner DB. HIV-1 Vpr and anti-inflammatory activity. DNA Cell Biol 2004, 23:239-247. 10.1089/104454904773819824, 15142381.
204. Venkatachari NJ, Majumder B, Ayyavoo V. Human immunodeficiency virus (HIV) type 1 Vpr induces differential regulation of T cell costimulatory molecules: direct effect of Vpr on T cell activation and immune function. Virology 2007, 358:347-356. 10.1016/j.virol.2006.08.030, 17023015.
205. Muthumani K, Hwang DS, Choo AY, Mayilvahanan S, Dayes NS, Thieu KP, Weiner DB. HIV-1 Vpr inhibits the maturation and activation of macrophages and dendritic cells in vitro. Int Immunol 2005, 17:103-116. 10.1093/intimm/dxh190, 15611322.
206. Muthumani K, Choo AY, Hwang DS, Dayes NS, Chattergoon M, Mayilvahanan S, Thieu KP, Buckley PT, Emmanuel J, Premkumar A, Weiner DB. HIV-1 Viral protein-r (Vpr) protects against lethal superantigen challenge while maintaining homeostatic T cell levels in vivo. Mol Ther 2005, 12:910-921. 10.1016/j.ymthe.2005.05.009, 16006193.
207. Auphan N, DiDonato JA, Rosette C, Helmberg A, Karin M. Immunosuppression by glucocorticoids: inhibition of NF-kappa B activity through induction of I kappa B synthesis. Science 1995, 270:286-290. 10.1126/science.270.5234.286, 7569976.
208. Scheinman RI, Cogswell PC, Lofquist AK, Baldwin AS, Jr. Role of transcriptional activation of I kappa B alpha in mediation of immunosuppression by glucocorticoids. Science 1995, 270:283-286. 10.1126/science.270.5234.283, 7569975.
209. Ayyavoo V, Mahboubi A, Mahalingam S, Ramalingam R, Kudchodkar S, Williams WV, Green DR, Weiner DB. HIV-1 Vpr suppresses immune activation and apoptosis through regulation of nuclear factor kappa B. Nat Med 1997, 3:1117-1123. 10.1038/nm1097-1117, 9334723.
210. Mirani M, Elenkov I, Volpi S, Hiroi N, Chrousos GP, Kino T. HIV-1 protein Vpr suppresses IL-12 production from human monocytes by enhancing glucocorticoid action: potential implications of Vpr coactivator activity for the innate and cellular immunity deficits observed in HIV-1 infection. J Immunol 2002, 169:6361-6368.
211. Muthumani K, Kudchodkar S, Papasavvas E, Montaner LJ, Weiner DB, Ayyavoo V. HIV-1 Vpr regulates expression of beta chemokines in human primary lymphocytes and macrophages. J Leukoc Biol 2000, 68:366-372.
212. Varin A, Decrion A, Sabbah E, Quivy V, Sire J, Van Lint C, Roques B, Aggarwal B, Herbein G. Synthetic Vpr protein activates activator protein-1, c-Jun N-terminal kinase, and NF-kappaB and stimulates HIV-1 transcription in promonocytic cells and primary macrophages. J Biol Chem 2005, 280:42557-42567. 10.1074/jbc.M502211200, 16243842.
213. Roux P, Alfieri C, Hrimech M, Cohen E, Tanner J. Activation of transcription factors NF-kappaB and NF-IL-6 by human immunodeficiency virus type 1 protein R (Vpr) induces interleukin-8 expression. J Virol 2000, 74:4658-4665. 10.1128/JVI.74.10.4658-4665.2000, 111986, 10775602.
214. Eckstein DA, Sherman MP, Penn ML, Chin PS, De Noronha CM, Greene WC, Goldsmith MA. HIV-1 Vpr enhances viral burden by facilitating infection of tissue macrophages but not nondividing CD4+ T cells. J Exp Med 2001, 194:1407-1419. 10.1084/jem.194.10.1407, 2193684, 11714748.
215. Lang SM, Weeger M, Stahl-Hennig C, Coulibaly C, Hunsmann G, Muller J, Muller-Hermelink H, Fuchs D, Wachter H, Daniel MM, et al. Importance of vpr for infection of rhesus monkeys with simian immunodeficiency virus. J Virol 1993, 67:902-912. 237444, 8380472.
216. Tzitzivacos DB, Tiemessen CT, Stevens WS, Papathanasopoulos MA. Viral genetic determinants of nonprogressive HIV type 1 subtype C infection in antiretroviral drug-naive children. AIDS Res Hum Retroviruses 2009, 25:1141-1148. 10.1089/aid.2009.0080, 19895210.
217. Jacquot G, Le Rouzic E, Maidou-Peindara P, Maizy M, Lefrere JJ, Daneluzzi V, Monteiro-Filho CM, Hong D, Planelles V, Morand-Joubert L, Benichou S. Characterization of the molecular determinants of primary HIV-1 Vpr proteins: impact of the Q65R and R77Q substitutions on Vpr functions. PLoS One 2009, 4:e7514. 10.1371/journal.pone.0007514, 2759284, 19838296.
218. Aquaro S, Svicher V, Schols D, Pollicita M, Antinori A, Balzarini J, Perno CF. Mechanisms underlying activity of antiretroviral drugs in HIV-1-infected macrophages: new therapeutic strategies. J Leukoc Biol 2006, 80:1103-1110. 10.1189/jlb.0606376, 16931601.
219. Dutta T, Agashe HB, Garg M, Balakrishnan P, Kabra M, Jain NK. Poly (propyleneimine) dendrimer based nanocontainers for targeting of efavirenz to human monocytes/macrophages in vitro. J Drug Target 2007, 15:89-98. 10.1080/10611860600965914, 17365278.
220. Vyas TK, Shah L, Amiji MM. Nanoparticulate drug carriers for delivery of HIV/AIDS therapy to viral reservoir sites. Expert Opin Drug Deliv 2006, 3:613-628. 10.1517/17425247.3.5.613, 16948557.
221. Swingler S, Mann AM, Zhou J, Swingler C, Stevenson M. Apoptotic killing of HIV-1-infected macrophages is subverted by the viral envelope glycoprotein. PLoS Pathog 2007, 3:1281-1290. 10.1371/journal.ppat.0030134, 2323301, 17907802.
222. Huang Y, Erdmann N, Peng H, Herek S, Davis JS, Luo X, Ikezu T, Zheng J. TRAIL-mediated apoptosis in HIV-1-infected macrophages is dependent on the inhibition of Akt-1 phosphorylation. J Immunol 2006, 177:2304-2313. 1892167, 16887991.
223. Chugh P, Bradel-Tretheway B, Monteiro-Filho CM, Planelles V, Maggirwar SB, Dewhurst S, Kim B. Akt inhibitors as an HIV-1 infected macrophage-specific anti-viral therapy. Retrovirology 2008, 5:11. 10.1186/1742-4690-5-11, 2265748, 18237430.
224. Kapasi AA, Coscia SA, Pandya MP, Singhal PC. Morphine modulates HIV-1 gp160-induced murine macrophage and human monocyte apoptosis by disparate ways. J Neuroimmunol 2004, 148:86-96. 10.1016/j.jneuroim.2003.11.015, 14975589.
225. Li G, Bukrinsky M, Zhao RY. HIV-1 viral protein R (Vpr) and its interactions with host cell. Curr HIV Res 2009, 7:178-183. 10.2174/157016209787581436, 19275587.
226. Liang D, Benko Z, Agbottah E, Bukrinsky M, Zhao RY. Anti-vpr activities of heat shock protein 27. Mol Med 2007, 13:229-239. 10.2119/2007-00004.Liang, 1906686, 17622316.
227. Iordanskiy S, Zhao Y, Dubrovsky L, Iordanskaya T, Chen M, Liang D, Bukrinsky M. Heat shock protein 70 protects cells from cell cycle arrest and apoptosis induced by human immunodeficiency virus type 1 viral protein R. J Virol 2004, 78:9697-9704. 10.1128/JVI.78.18.9697-9704.2004, 515005, 15331702.
228. Iordanskiy S, Zhao Y, DiMarzio P, Agostini I, Dubrovsky L, Bukrinsky M. Heat-shock protein 70 exerts opposing effects on Vpr-dependent and Vpr-independent HIV-1 replication in macrophages. Blood 2004, 104:1867-1872. 10.1182/blood-2004-01-0081, 15166037.
229. Yedavalli VS, Shih HM, Chiang YP, Lu CY, Chang LY, Chen MY, Chuang CY, Dayton AI, Jeang KT, Huang LM. Human immunodeficiency virus type 1 Vpr interacts with antiapoptotic mitochondrial protein HAX-1. J Virol 2005, 79:13735-13746. 10.1128/JVI.79.21.13735-13746.2005, 1262574, 16227293.
230. Gibellini D, Re MC, Ponti C, Vitone F, Bon I, Fabbri G, Grazia Di Iasio M, Zauli G. HIV-1 Tat protein concomitantly down-regulates apical caspase-10 and up-regulates c-FLIP in lymphoid T cells: a potential molecular mechanism to escape TRAIL cytotoxicity. J Cell Physiol 2005, 203:547-556. 10.1002/jcp.20252, 15573381.
231. Haffar OK, Smithgall MD, Popov S, Ulrich P, Bruce AG, Nadler SG, Cerami A, Bukrinsky MI. CNI-H0294, a nuclear importation inhibitor of the human immunodeficiency virus type 1 genome, abrogates virus replication in infected activated peripheral blood mononuclear cells. Antimicrob Agents Chemother 1998, 42:1133-1138. 105758, 9593140.
232. Suzuki T, Yamamoto N, Nonaka M, Hashimoto Y, Matsuda G, Takeshima SN, Matsuyama M, Igarashi T, Miura T, Tanaka R, et al. 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 2009, 380:838-843. 10.1016/j.bbrc.2009.01.180, 19338763.
233. 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, 67:7229-7237. 238185, 8230445.
234. Yao XJ, Kobinger G, Dandache S, Rougeau N, Cohen E. HIV-1 Vpr-chloramphenicol acetyltransferase fusion proteins: sequence requirement for virion incorporation and analysis of antiviral effect. Gene Ther 1999, 6:1590-1599. 10.1038/sj.gt.3300988, 10490769.
235. Ao Z, Yu Z, Wang L, Zheng Y, Yao X. Vpr14-88-Apobec3G fusion protein is efficiently incorporated into Vif-positive HIV-1 particles and inhibits viral infection. PLoS ONE 2008, 3:e1995. 10.1371/journal.pone.0001995, 2288674, 18414671.
236. Mariani R, Chen D, Schrofelbauer B, Navarro F, Konig R, Bollman B, Munk C, Nymark-McMahon H, Landau NR. Species-specific exclusion of APOBEC3G from HIV-1 virions by Vif. Cell 2003, 114:21-31. 10.1016/S0092-8674(03)00515-4, 12859895.
237. Sheehy AM, Gaddis NC, Choi JD, Malim MH. Isolation of a human gene that inhibits HIV-1 infection and is suppressed by the viral Vif protein. Nature 2002, 418:646-650. 10.1038/nature00939, 12167863.
238. Stewart SA, Poon B, Jowett JB, Xie Y, Chen IS. Lentiviral delivery of HIV-1 Vpr protein induces apoptosis in transformed cells. Proc Natl Acad Sci USA 1999, 96:12039-12043. 10.1073/pnas.96.21.12039, 18408, 10518572.
239. Shimura M, Tanaka Y, Nakamura S, Minemoto Y, Yamashita K, Hatake K, Takaku F, Ishizaka Y. Micronuclei formation and aneuploidy induced by Vpr, an accessory gene of human immunodeficiency virus type 1. Faseb J 1999, 13:621-637.