Molecules and Cells

  • 제21권1호
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  • Pages.7-20
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  • 2006
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  • 1016-8478(pISSN)
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  • 0219-1032(eISSN)
한국분자세포생물학회 (Korean Society for Molecular and Cellular Biology)
권호 표지

Role of HIV Vpr as a Regulator of Apoptosis and an Effector on Bystander Cells

  • Moon, Ho Suck (Department of Genetic Engineering, Faculty of Life Science and Technology, Sungkyunkwan University) ;
  • Yang, Joo-Sung (Department of Genetic Engineering, Faculty of Life Science and Technology, Sungkyunkwan University)
  • 투고 : 2006.02.07
  • 심사 : 2006.02.10
  • 발행 : 2006.02.28
⟨ 이전 논문 다음 논문 ⟩

초록

The major event in human immunodeficiency virus type 1 (HIV-1) infection is the death of many cells related to host immune response. The demise of these cells is normally explained by cell suicide mechanism, apoptosis. Interestingly, the decrease in the number of immune cells, such as non-CD4+ cells as well as CD4+ T cells, in HIV infection usually occurs in uninfected bystander cells, not in directly infected cells. It has, therefore, been suggested that several soluble factors, including viral protein R (Vpr), are released from the infected cells and induce the death of bystander cells. Some studies show that Vpr interacts directly with adenine nucleotide translocator (ANT) to induce mitochondrial membrane permeabilization (MMP). The MMP results in release of some apoptogenic factors such as cytochrome-c (cyt-c) and apoptosis-inducing factor (AIF). Vpr also has indirect effect on mitochondria through enhancing the level of caspase-9 transcription and suppressing nuclear factor-kappa B (NF-${\kappa}B$). The involvement of p53 in Vpr-induced apoptosis remains to be studied. On the other hand, low level of Vpr expression has anti-apoptotic effect, whereas it's high level of expression induces apoptosis. Extracellular Vpr also exhibits cytotoxicity to uninfected bystander cells through apoptotic or necrotic mechanism. The facts that Vpr has cytotoxic effect on both infected cells and bystander cells, and that it exhibits both proand anti-apoptotic activity may explain its role in viral survival and disease progression.

키워드

과제정보

연구 과제 주관 기관 : Korea Science and Engineering Foundation

참고문헌

  1. Amendola, A., Gougeon, M. L., Poccia, F., Bondurand, A., Fesus, L., et al. (1996) Induction of 'tissue' transglutaminase in HIV pathogenesis: evidence for high rate of apoptosis of CD4+ T lymphocytes and accessory cells in lymphoid tissues. Proc. Natl. Acad. Sci. USA 93, 11057−11062
  2. Anderson, R. W., Ascher, M. S., and Sheppard, H. W. (1998) Direct HIV cytopathicity cannot account for CD4 decline in AIDS in the presence of homeostasis: a worst-case dynamic analysis. J. Acquir Immune Defic. Syndr. Hum. Retrovirol. 17, 245−252 https://doi.org/10.1097/00042560-199803010-00010
  3. Arunagiri, C. K., Macreadie, I. G., Hewish, D. R., Azad, A. A. (1997) A C-terminal domain of HIV-1-accessory protein Vpr is involved in penetration, mitochondrial dysfunction and apoptosis of human CD4(+) lymphocytes. Apoptosis 2, 69−76 https://doi.org/10.1023/A:1026487609215
  4. Ascher, M. S., Sheppard, H. W., Anderson, R. W., Krowka, J. F., and Bremermann, H. J. (1995) HIV results in the frame. Paradox remains. Nature 375, author reply 198
  5. Auphan, N., DiDonato, J. A., Rosette, C., Helmberg, A., and Karin, M. (1995) Immunosuppression by glucocorticoids: inhibition of NF-kappa B activity through induction of I kappa B synthesis. Science 270, 286−290 https://doi.org/10.1126/science.270.5234.286
  6. Ayyavoo, V., Mahboubi, A., Mahalingam, S., Ramalingam, R., Kudchodkar, S., et al. (1997) HIV-1 Vpr suppresses immune activation and apoptosis through regulation of nuclear factor kappa B. Nat. Med. 3, 1117−1123 https://doi.org/10.1038/nm1097-1117
  7. Azad, A. A. (2000) 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. 267, 677−685 https://doi.org/10.1006/bbrc.1999.1919
  8. Beaulieu, S., Kessous, A., Landry, D., Montplaisir, S., Bergeron, D., et al. (1996) In vitro characterization of purified human thymic dendritic cells infected with human immunodeficiency virus type 1. Virology 222, 214−226
  9. Beg, A. A., Sha, W. C., Bronson, R. T., and Baltimore, D. (1995) Constitutive NF-kappa B activation, enhanced granulopoiesis, and neonatal lethality in I kappa B alpha-deficient mice. Genes Dev. 9, 2736−2746 https://doi.org/10.1101/gad.9.22.2736
  10. Beg, A. A. and Baltimore, D. (1996) An essential role for NFkappaB in preventing TNF-alpha-induced cell death. Science 274, 782−784 https://doi.org/10.1126/science.274.5288.782
  11. Bofill, M., Gombert, W., Borthwick, N. J., Akbar, A. N., McLaughlin, J. E., et al. (1995) Presence of CD3+CD8+Bcl- 2(low) lymphocytes undergoing apoptosis and activated macrophages in lymph nodes of HIV-1+ patients. Am. J. Pathol. 146, 1542−1555
  12. Borrow, P., Lewicki, H., Hahn, B. H., Shaw, G. M., and Oldstone, M. B. (1994) Virus-specific CD8+ cytotoxic Tlymphocyte activity associated with control of viremia in primary human immunodeficiency virus type 1 infection. J. Virol. 68, 6103−10
  13. Bouhamdan, M., Benichou, S., Rey, F., Navarro, J. M., Agostini, I., et al. (1996) Human immunodeficiency virus type 1 Vpr protein binds to the uracil DNA glycosylase DNA repair enzyme. J. Virol. 70, 697−704
  14. BouHamdan, M., Kulkosky, J., Duan, L. X., and Pomerantz, R. J. (2000) Inhibition of HIV-1 replication and infectivity by expression of a fusion protein, VPR-anti-integrase singlechain variable fragment (SFv): intravirion molecular therapies. J. Hum. Virol. 3, 6−15
  15. Brack-Werner, R. (1999) Astrocytes: HIV cellular reservoirs and important participants in neuropathogenesis. AIDS 13, 1−22 https://doi.org/10.1097/00002030-199901140-00003
  16. Bukrinsky, M. and Adzhubei, A. (1999) Viral protein R of HIV- 1. Rev. Med. Virol. 9, 39−49 https://doi.org/10.1002/(SICI)1099-1654(199901/03)9:1<39::AID-RMV235>3.0.CO;2-3
  17. Carbonari, M., Cibati, M., Cherchi, M., Sbarigia, D., Pesce, A. M., et al. (1994) Detection and characterization of apoptotic peripheral blood lymphocytes in human immunodeficiency virus infection and cancer chemotherapy by a novel flow immunocytometric method. Blood 83, 1268−1277
  18. Carbonari, M., Cibati, M., Pesce, A. M., Sbarigia, D., Grossi, P., et al. (1995) Frequency of provirus-bearing CD4+ cells in HIV type 1 infection correlates with extent of in vitro apoptosis of CD8+ but not of CD4+ cells. AIDS Res. Hum. Retroviruses 11, 789−794 https://doi.org/10.1089/aid.1995.11.789
  19. Carbonari, M., Pesce, A. M., Cibati, M., Modica, A., Dell'Anna, L., et al. (1997) Death of bystander cells by a novel pathway involving early mitochondrial damage in human immunodeficiency virus-related lymphadenopathy. Blood 90, 209−216
  20. Chang, L. J., Chen, C. H., Urlacher, V., and Lee, T. Z. (2000) Differential apoptosis effects of primate lentiviral Vpr and Vpx in mammalian cells. J. Biomed. Sci. 7, 322−333
  21. Chen, H., Yip, Y. K., George, I., Tyorkin, M., Salik, E., et al. (1998) Chronically HIV-1-infected monocytic cells induce apoptosis in cocultured T cells. J. Immunol. 161, 4257−4267
  22. Chen, C., Edelstein, L. C., and Gelinas, C. (2000) The Rel/NFkappaB family directly activates expression of the apoptosis inhibitor Bcl-x(L). Mol. Cell. Biol. 20, 2687−2695 https://doi.org/10.1128/MCB.20.8.2687-2695.2000
  23. Chia, W. K., Freedman, J., Li, X., Salit, I., Kardish, M., et al. (1995) Programmed cell death induced by HIV type 1 antigen stimulation is associated with a decrease in cytotoxic T lymphocyte activity in advanced HIV type 1 infection. AIDS Res. Hum. Retroviruses 11, 249−256
  24. Cloyd, M. W. and Lynn, W. S. (1991) Perturbation of host-cell membrane is a primary mechanism of HIV cytopathology. Virology 181, 500−511 https://doi.org/10.1016/0042-6822(91)90882-C
  25. Cohen, E. A., Terwilliger, E. F., Jalinoos, Y., Proulx, J., Sodroski, J. G., et al. (1990) Identification of HIV-1 vpr product and function. J. Acquir. Immune Defic. Syndr. 3, 11−18
  26. Conti, L., Rainaldi, G., Matarrese, P., Varano, B., Rivabene, R., et al. (1998) 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. 187, 403−413
  27. Conti, L., Matarrese, P., Varano, B., Gauzzi, M. C., Sato, A., et al. (2000) Dual role of the HIV-1 vpr protein in the modulation of the apoptotic response of T cells. J. Immunol. 165, 3293−3300
  28. Daugas, E., Susin, S. A., Zamzami, N., Ferri, K. F., Irinopoulou, T., et al. (2000) Mitochondrio-nuclear translocation of AIF in apoptosis and necrosis. FASEB J. 14, 729−739
  29. Deveraux, Q. L., Takahashi, R., Salvesen, G.. S., and Reed, J. C. (1997) X-linked IAP is a direct inhibitor of cell-death proteases. Nature 388, 300-304 https://doi.org/10.1038/40901
  30. Deveraux, Q. L., Roy, N., Stennicke, H. R., Van Arsdale, T., Zhou, Q., et al. (1998) IAPs block apoptotic events induced by caspase-8 and cytochrome c by direct inhibition of distinct caspases. EMBO J. 17, 2215−2223
  31. Emerman, M., Bukrinsky, M. I., and Stevenson, M. (1994) HIV- 1 infection of non-dividing cells. Nature 369, 107−108
  32. Finkel, T. H., Tudor-Williams, G.., Banda, N. K., Cotton, M. F., Curiel, T., et al. (1995) Apoptosis occurs predominantly in bystander cells and not in productively infected cells of HIVand SIV-infected lymph nodes. Nat. Med. 1, 129−134 https://doi.org/10.1038/nm0295-129
  33. Fukumori, T., Akari, H., Iida, S., Hata, S., Kagawa, S., et al. (1998) The HIV-1 Vpr displays strong anti-apoptotic activity. FEBS Lett. 432, 17−20 https://doi.org/10.1016/S0014-5793(98)00824-2
  34. Fukumori, T., Akari, H., Yoshida, A., Fujita, M., Koyama, A. H., et al. (2000) Regulation of cell cycle and apoptosis by human immunodeficiency virus type 1 Vpr. Microbes Infect. 2, 1011−1017
  35. Gaynor, E. M. and Chen, I. S. (2001) Analysis of apoptosis induced by HIV-1 Vpr and examination of the possible role of the hHR23A protein. Exp. Cell. Res. 267, 243−257
  36. Gougeon, M. L., Garcia, S., Heeney, J., Tschopp, R., Lecoeur, H., et al. (1993) Programmed cell death in AIDS-related HIV and SIV infections. AIDS Res. Hum. Retroviruses 9, 553−563 https://doi.org/10.1089/aid.1993.9.553
  37. Gougeon, M. L., Lecoeur, H., Dulioust, A., Enouf, M. G., Crouvoiser, M., et al. (1996) Programmed cell death in peripheral lymphocytes from HIV-infected persons: increased susceptibility to apoptosis of CD4 and CD8 T cells correlates with lymphocyte activation and with disease progression. J. Immunol. 156, 3509−3520
  38. Goh, W. C., Rogel, M. E., Kinsey, C. M., Michael, S. F., Fultz, P. N., 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 https://doi.org/10.1038/nm0198-065
  39. Groux, H., Torpier, G.., Monte, D., Mouton, Y., Capron, A., et al. (1992) Activation-induced death by apoptosis in CD4+ T cells from human immunodeficiency virus-infected asymptomatic individuals. J. Exp. Med. 175, 331−340 https://doi.org/10.1084/jem.175.2.331
  40. He, J., Choe, S., Walker, R., Di Marzio, P., Morgan, D. O., et al. (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
  41. Heinzinger, N. K., Bukinsky, M. I., Haggerty, S. A., Ragland, A. M., Kewalramani, V., 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. USA 91, 7311−7315
  42. Ho, D. D., Neumann, A. U., Perelson, A. S., Chen, W., Leonard, J. M., et al. (1995) Rapid turnover of plasma virions and CD4 lymphocytes in HIV-1 infection. Nature 373, 123−126 https://doi.org/10.1038/373123a0
  43. Hrimech, M., Yao, X. J., Bachand, F., Rougeau, N., and Cohen, E. A. (1999) Human immunodeficiency virus type 1 (HIV-1) Vpr functions as an immediate-early protein during HIV-1 infection. J. Virol. 73, 4101−4109
  44. Huang, M. B., Weeks, O., Zhao, L. J., Saltarelli, M., and Bond, V. C. (2000) Effects of extracellular human immunodeficiency virus type 1 vpr protein in primary rat cortical cell cultures. J. Neurovirol. 6, 202−220
  45. Jacotot, E., Ravagnan, L., Loeffler, M., Ferri, K. F., Vieira, H. L., 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, 33−46 https://doi.org/10.1084/jem.191.1.33
  46. Jacotot, E., Ferri, K. F., El Hamel, C., Brenner, C., Druillennec, S., 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 https://doi.org/10.1084/jem.193.4.509
  47. Janossy, G., Borthwick, N., Lomnitzer, R., Medina, E., Squire, S. B., et al. (1993) Lymphocyte activation in HIV-1 infection. I. Predominant proliferative defects among CD45R0+ cells of the CD4 and CD8 lineages. AIDS 7, 613−624 https://doi.org/10.1097/00002030-199311002-00003
  48. Jowett, J. B., Planelles, V., Poon, B., Shah, N. P., Chen, M. L., et al. (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
  49. Katsikis, P. D., Wunderlich, E. S., Smith, C. A., Herzenberg, L. A., and Herzenberg, L. A. (1995) Fas antigen stimulation induces marked apoptosis of T lymphocytes in human immunodeficiency virus-infected individuals. J. Exp. Med. 181, 2029−2036 https://doi.org/10.1084/jem.181.6.2029
  50. Kerr, J. F., Wyllie, A. H., and Currie, A. R. (1972) Apoptosis: a basic biological phenomenon with wide-ranging implications in tissue kinetics. Br. J. Cancer 26, 239−257
  51. Kino, T., Gragerov, A., Kopp, J. B., Stauber, R. H., Pavlakis, G. N., et al. (1999) The HIV-1 virion-associated protein vpr is a coactivator of the human glucocorticoid receptor. J. Exp. Med. 189, 51−62 https://doi.org/10.1084/jem.189.1.51
  52. Kino, T., Gragerov, A., Slobodskaya, O., Tsopanomichalou, M., Chrousos, G.. P., et al. (2002) 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. 76, 9724−9734 https://doi.org/10.1128/JVI.76.19.9724-9734.2002
  53. Kluck, R. M., Bossy-Wetzel, E., Green, D. R., and Newmeyer, D. D. (1997) The release of cytochrome c from mitochondria: a primary site for Bcl-2 regulation of apoptosis. Science 275, 1132−1136
  54. Kroemer, G. and Reed, J. C. (2000) Mitochondrial control of cell death. Nat. Med. 6, 513−519
  55. Levy, D. N., Fernandes, L. S., Williams, W. V., and Weiner, D. B. (1993a) Induction of cell differentiation by human immunodeficiency virus 1 vpr. Cell 72, 541−550
  56. Levy, J. A. (1993b) Pathogenesis of human immunodeficiency virus infection. Microbiol. Rev. 57, 183−289
  57. Levy, D. N., Refaeli, Y., MacGregor, R. R., and Weiner, D. B. (1994) Serum Vpr regulates productive infection and latency of human immunodeficiency virus type 1. Proc. Natl. Acad. Sci. USA 91, 10873−10877
  58. Levy, D. N., Refaeli, Y., and Weiner, D. B. (1995) Extracellular Vpr protein increases cellular permissiveness to human immunodeficiency virus replication and reactivates virus from latency. J. Virol. 69, 1243−1252
  59. Lewis, D. E., Tang, D. S., Adu-Oppong, A., Schober, W., and Rodgers, J. R. (1994) Anergy and apoptosis in CD8+ T cells from HIV-infected persons. J. Immunol. 153, 412−420
  60. Li, Z. W., Chu, W., Hu, Y., Delhase, M., Deerinck, T., et al. (1999) The IKKbeta subunit of IkappaB kinase (IKK) is essential for nuclear factor kappaB activation and prevention of apoptosis. J. Exp. Med. 189, 1839−1845
  61. Lifson, J. D., Feinberg, M. B., Reyes, G. R., Rabin, L., Banapour, B., et al. (1986) Induction of CD4-dependent cell fusion by the HTLV-III/LAV envelope glycoprotein. Nature 323, 725−8 https://doi.org/10.1038/323725a0
  62. Liu, Z. G., Hsu, H., Goeddel, D. V., and Karin, M. (1996) Dissection of TNF receptor 1 effector functions: JNK activation is not linked to apoptosis while NF-kappaB activation prevents cell death. Cell 87, 565−576
  63. Lu, Y. L., Spearman, P., and Ratner, L. (1993) Human immunodeficiency virus type 1 viral protein R localization in infected cells and virions. J. Virol. 67, 6542−6550
  64. Macreadie, I. G., Castelli, L. A., Hewish, D. R., Kirkpatrick, A., Ward, A. C., et al. (1995) A domain of human immunodeficiency virus type 1 Vpr containing repeated H(S/F)RIG amino acid motifs causes cell growth arrest and structural defects. Proc. Natl. Acad. Sci. USA 92, 2770−2774
  65. Macreadie, I. G., Arunagiri, C. K., Hewish, D. R., White, J. F., and Azad, A. A. (1996) Extracellular addition of a domain of HIV-1 Vpr containing the amino acid sequence motif H(S/F)RIG causes cell membrane permeabilization and death. Mol. Microbiol. 19, 1185−1192 https://doi.org/10.1111/j.1365-2958.1996.tb02464.x
  66. Macreadie, I. G., Thorburn, D. R., Kirby, D. M., Castelli, L. A., de Rozario, N. L., et al. (1997) HIV-1 protein Vpr causes gross mitochondrial dysfunction in the yeast Saccharomyces cerevisiae. FEBS Lett. 410, 145−149
  67. Meyaard, L., Schuitemaker, H., and Miedema, F. (1993) T-cell dysfunction in HIV infection: anergy due to defective antigen- presenting cell function- Immunol. Today 14, 161−164 https://doi.org/10.1016/0167-5699(93)90279-T
  68. Muthumani, K., Zhang, D., Hwang, D. S., Kudchodkar, S., Dayes, N. S., et al. (2002a) Adenovirus encoding HIV-1 Vpr activates caspase 9 and induces apoptotic cell death in both p53 positive and negative human tumor cell lines. Oncogene 21, 4613−4625 https://doi.org/10.1038/sj.onc.1205549
  69. Muthumani, K., Hwang, D. S., Desai, B. M., Zhang, D., Dayes, N., et al. (2002b) HIV-1 Vpr induces apoptosis through caspase 9 in T cells and peripheral blood mononuclear cells. J. Biol. Chem. 277, 37820−31 https://doi.org/10.1074/jbc.M205313200
  70. Nardelli, B., Gonzalez, C. J., Schechter, M., and Valentine, F. T. (1995) CD4+ blood lymphocytes are rapidly killed in vitro by contact with autologous human immunodeficiency virusinfected cells. Proc. Natl. Acad. Sci. USA 92, 7312−7316
  71. Nath, A and Geiger, J. (1998) Neurobiological aspects of human immunodeficiency virus infection: neurotoxic mechanisms. Prog. Neurobiol. 54, 19−33
  72. Navia, B. A., Jordan, B. D., and Price, R. W. (1986) The AIDS dementia complex: I. Clinical features. Ann. Neurol. 19, 517−524
  73. Nottet, H. S. and Gendelman, H. E. (1995) Unraveling the neuroimmune mechanisms for the HIV-1-associated cognitive/ motor complex. Immunol. Today 16, 441−448 https://doi.org/10.1016/0167-5699(95)80022-0
  74. Nottet, H. S. (1999) Interactions between macrophages and brain microvascular endothelial cells: role in pathogenesis of HIV-1 infection and blood-brain barrier function. J. Neurovirol. 5, 659−669 https://doi.org/10.3109/13550289909021294
  75. Parone, P. A., James, D., and Martinou, J. C. (2002) Mitochondria: regulating the inevitable. Biochimie. 84, 105−111
  76. Patel, C. A., Mukhtar, M., and Pomerantz, R. J. (2000) Human immunodeficiency virus type 1 Vpr induces apoptosis in human neuronal cells. J. Virol. 74, 9717−9726
  77. Paxton, W., Connor, R. I., and Landau, N. R. (1993) Incorporation of Vpr into human immunodeficiency virus type 1 virions: requirement for the p6 region of gag and mutational analysis. J. Virol. 67, 7229−7237
  78. Perelson, A. S., Neumann, A. U., Markowitz, M., Leonard, J. M., and Ho, D. D. (1996) HIV-1 dynamics in vivo: virion clearance rate, infected cell life-span, and viral generation time. Science 271, 1582−1586 https://doi.org/10.1126/science.271.5255.1582
  79. Piller, S. C., Ewart, G. D., Premkumar, A., Cox, G. B., and Gage, P. W. (1996) Vpr protein of human immunodeficiency virus type 1 forms cation-selective channels in planar lipid bilayers. Proc. Natl. Acad. Sci. USA 93, 111−115
  80. Piller, S. C., Jans, P., Gage, P. W., and Jans, D. A. (1998) 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 95, 4595−4600
  81. Piller, S. C., Ewart, G. D., Jans, D. A., Gage, P. W., and Cox, G. B. (1999) The amino-terminal region of Vpr from human immunodeficiency virus type 1 forms ion channels and kills neurons. J. Virol. 73, 4230−4238
  82. Poon, B., Jowett, J. B., Stewart, S. A., Armstrong, R. W., Rishton, G. M., et al. (1997) Human immunodeficiency virus type 1 vpr gene induces phenotypic effects similar to those of the DNA alkylating agent, nitrogen mustard. J. Virol. 71, 3961− 3971
  83. Poon, B., Grovit-Ferbas, K., Stewart, S. A., and Chen, I. S. (1998) Cell cycle arrest by Vpr in HIV-1 virions and insensitivity to antiretroviral agents. Science 281, 266−269 https://doi.org/10.1126/science.281.5374.266
  84. Price, R. W., Brew, B., Sidtis, J., Rosenblum, M., Scheck, A. C., et al. (1988) The brain in AIDS: central nervous system HIV- 1 infection and AIDS dementia complex. Science 239, 586−592 https://doi.org/10.1126/science.3277272
  85. Re, M. C., Zauli, G., Gibellini, D., Furlini, G., Ramazzotti, E., et al. (1993) Uninfected haematopoietic progenitor (CD34+) cells purified from the bone marrow of AIDS patients are committed to apoptotic cell death in culture. AIDS 7, 1049−1055 https://doi.org/10.1097/00002030-199311002-00003
  86. 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
  87. Reddy, M. M., Goetz, R. R., Gorman, J. M., Grieco, M. H., Chess, L., et al. (1991) Human immunodeficiency virus type- 1 infection of homosexual men is accompanied by a decrease in circulating B cells. J. Acquir. Immune Defic. Syndr. 4, 428−434
  88. Refaeli, Y., Levy, D. N., and Weiner, D. B. (1995) The glucocorticoid receptor type II complex is a target of the HIV-1 vpr gene product. Proc. Natl. Acad. Sci. USA 92, 3621−3625
  89. de Rocquigny, H., Caneparo, A., Delaunay, T., Bischerour, J., Mouscadet, J. F., et al. (2000) Interactions of the C-terminus of viral protein R with nucleic acids are modulated by its Nterminus. Eur. J. Biochem. 267, 3654−3660
  90. Roshal, M., Zhu, Y., and Planelles, V. (2001) Apoptosis in AIDS. Apoptosis 6, 103−116
  91. Roumier, T., Vieira, H. L., Castedo, M., Ferri, K. F., Boya, P., et al. (2002) The C-terminal moiety of HIV-1 Vpr induces cell death via a caspase-independent mitochondrial pathway. Cell Death Differ. 9, 1212−1219 https://doi.org/10.1038/sj.cdd.4401089
  92. Samuelsson, A., Sonnerborg, A., Heuts, N., Coster, J., and Chiodi, F. (1997) Progressive B cell apoptosis and expression of Fas ligand during human immunodeficiency virus type 1 infection. AIDS Res. Hum. Retroviruses 13, 1031-1038 https://doi.org/10.1089/aid.1997.13.1031
  93. Schuler, M. and Green, D. R. (2001) Mechanisms of p53- dependent apoptosis. Biochem. Soc. Trans. 29, 684−688 https://doi.org/10.1042/BST0290684
  94. Selig, L., Benichou, S., Rogel, M. E., Wu, L. I., Vodicka, M. A., et al. (1997) Uracil DNA glycosylase specifically interacts with Vpr of both human immunodeficiency virus type 1 and simian immunodeficiency virus of sooty mangabeys, but binding does not correlate with cell cycle arrest. J. Virol. 71, 4842−4846
  95. Shimura, M., Tanaka, Y., Nakamura, S., Minemoto, Y., Yamashita, K., et al. (1999a) Micronuclei formation and aneuploidy induced by Vpr, an accessory gene of human immunodeficiency virus type 1. FASEB J. 13, 621−637
  96. Shimura, M., Onozuka, Y., Yamaguchi, T., Hatake, K., Takaku, F., et al. (1999b) Micronuclei formation with chromosome breaks and gene amplification caused by Vpr, an accessory gene of human immunodeficiency virus. Cancer Res. 59, 2259−2264
  97. Shostak, L. D., Ludlow, J., Fisk, J., Pursell, S., Rimel, B. J., et al. (1999) Roles of p53 and caspases in the induction of cell cycle arrest and apoptosis by HIV-1 vpr. Exp. Cell. Res. 251, 156−165 https://doi.org/10.1006/excr.1999.4568
  98. Sodroski, J., Goh, W. C., Rosen, C., Campbell, K., and Haseltine, W. A. (1986) Role of the HTLV-III/LAV envelope in syncytium formation and cytopathicity. Nature 322, 470− 474 https://doi.org/10.1038/322470a0
  99. 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
  100. 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. USA 96, 12039−12043
  101. Stewart, S. A., Poon, B., Song, J. Y., and Chen, I. S. (2000) Human immunodeficiency virus type 1 vpr induces apoptosis through caspase activation. J. Virol. 74, 3105−3111
  102. Su, L., Kaneshima, H., Bonyhadi, M., Salimi, S., Kraft, D., et al. (1995) HIV-1-induced thymocyte depletion is associated with indirect cytopathogenicity and infection of progenitor cells in vivo. Immunity 2, 25−36 https://doi.org/10.1016/1074-7613(95)90076-4
  103. Susin, S. A., Lorenzo, H. K., Zamzami, N., Marzo, I., Snow, B. E., et al. (1999) Molecular characterization of mitochondrial apoptosis-inducing factor. Nature 397, 441−446 https://doi.org/10.1038/16110
  104. Susin, S. A., Daugas, E., Ravagnan, L., Samejima, K., Zamzami, N., et al. (2000) Two distinct pathways leading to nuclear apoptosis. J. Exp. Med. 192, 571−580
  105. Tanaka, M., Fuentes, M. E., Yamaguchi, K., Durnin, M. H., Dalrymple, S. A., et al. (1999) Embryonic lethality, liver degeneration, and impaired NF-kappa B activation in IKKbeta- deficient mice. Immunity 10, 421−429 https://doi.org/10.1016/S1074-7613(00)80042-4
  106. Tristem, M., Marshall, C., Karpas, A., and Hill, F. (1992) Evolution of the primate lentiviruses: evidence from vpx and vpr. EMBO J. 11, 3405−3412
  107. Tristem, M., Purvis, A., and Quicke, D. L. (1998) Complex evolutionary history of primate lentiviral vpr genes. Virology 240, 232−237
  108. Tungaturthi, P. K., Sawaya, B. E., Singh, S. P., Tomkowicz, B., Ayyavoo, V., et al. (2003) Role of HIV-1 Vpr in AIDS pathogenesis: relevance and implications of intravirion, intracellular and free Vpr. Biomed Pharmacother. 57, 20−24 https://doi.org/10.1016/S0753-3322(02)00328-1
  109. Vander Heiden, M. G., Chandel, N. S., Williamson, E. K., Schumacker, P. T., and Thompson, C. B. (1997) Bcl-xL regulates the membrane potential and volume homeostasis of mitochondria. Cell 91, 627−637 https://doi.org/10.1016/S0092-8674(00)80450-X
  110. Veazey, R. S., DeMaria, M., Chalifoux, L. V., Shvetz, D. E., Pauley, D. R., et al. (1998) Gastrointestinal tract as a major site of CD4+ T cell depletion and viral replication in SIV infection. Science 280, 427−431
  111. Wang, C. Y., Mayo, M. W., Korneluk, R. G., Goeddel, D. V., and Baldwin, A. S. Jr. (1998) NF-kappaB antiapoptosis: induction of TRAF1 and TRAF2 and c-IAP1 and c-IAP2 to suppress caspase-8 activation. Science 281, 1680−1683 https://doi.org/10.1126/science.281.5383.1680
  112. Wang, C. Y., Cusack, J. C. Jr., Liu, R., and Baldwin, A. S. Jr. (1999) Control of inducible chemoresistance: enhanced antitumor therapy through increased apoptosis by inhibition of NF-kappaB. Nat. Med. 5, 412−417 https://doi.org/10.1038/7410
  113. Watanabe, N., Yamaguchi, T., Akimoto, Y., Rattner, J. B., Hirano, H., et al. (2000) Induction of M-phase arrest and apoptosis after HIV-1 Vpr expression through uncoupling of nuclear and centrosomal cycle in HeLa cells. Exp. Cell Res. 258, 261−269 https://doi.org/10.1006/excr.2000.4908
  114. Wei, X., Ghosh, S. K., Taylor, M. E., Johnson, V. A., Emini, E. A., et al. (1995) Viral dynamics in human immunodeficiency virus type 1 infection. Nature 373, 117−122 https://doi.org/10.1038/373117a0
  115. Withers-Ward, E. S., Jowett, J. B., Stewart, S. A., Xie, Y. M., Garfinkel, A., et al. (1997) Human immunodeficiency virus type 1 Vpr interacts with HHR23A, a cellular protein implicated in nucleotide excision DNA repair. J. Virol. 71, 9732− 9742
  116. Yang, J., Liu, X., Bhalla, K., Kim, C. N., Ibrado, A. M., et al. (1997) Prevention of apoptosis by Bcl-2: release of cyto chrome c from mitochondria blocked. Science 275, 1129− 1132 https://doi.org/10.1126/science.275.5303.1129
  117. Yao, X. J., Mouland, A. J., Subbramanian, R. A., Forget, J., Rougeau, N., 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
  118. Yedavalli, V. S., Shih, H. M., Chiang, Y. P., Lu, C. Yl, Chang, L. Y., et al. (2005) Human immunodeficiency virus type 1 Vpr interacts with antiapoptotic mitochondrial protein HAX-1. J Virol. 79, 13735−13746 https://doi.org/10.1128/JVI.79.21.13735-13746.2005
  119. Zhang, S., Pointer, D., Singer, G., Feng, Y., Park, K., et al. (1998) Direct binding to nucleic acids by Vpr of human immunodeficiency virus type 1. Gene 212, 157−166 https://doi.org/10.1016/S0378-1119(98)00178-4
  120. Zhu, Y., Gelbard, H. A., Roshal, M., Pursell, S., Jamieson, B. D., et al. (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
  121. Zhu, Y., Roshal, M., Li, F., Blackett, J., and Planelles, V. (2003) Upregulation of survivin by HIV-1 Vpr. Apoptosis 8, 71−79 https://doi.org/10.1023/A:1021653119934