1887

Abstract

AIDS, caused by the retroviruses human immunodeficiency virus type 1 and type 2 (HIV-1 and HIV-2), has reached pandemic proportions. Therefore, it is critical to understand how HIV causes AIDS so that appropriate therapies can be formulated. Primarily, HIV infects and kills CD4 T lymphocytes, which function as regulators and amplifiers of the immune response. In the absence of effective anti-retroviral therapy, the hallmark decrease in CD4 T lymphocytes during AIDS results in a weakened immune system, impairing the body's ability to fight infections or certain cancers such that death eventually ensues. The major mechanism for CD4 T cell depletion is programmed cell death (apoptosis), which can be induced by HIV through multiple pathways. Death of HIV-infected cells can result from the propensity of infected lymphocytes to form short-lived syncytia or from an increased susceptibility of the cells to death. However, the apoptotic cells appear to be primarily uninfected bystander cells and are eradicated by two different mechanisms: either a Fas-mediated mechanism during activation-induced cell death (AICD), or as a result of HIV proteins (Tat, gp120, Nef, Vpu) released from infected cells stimulating apoptosis in uninfected bystander cells. There is also evidence that as AIDS progresses cytokine dysregulation occurs, and the overproduction of type-2 cytokines (IL-4, IL-10) increases susceptibility to AICD whereas type-1 cytokines (IL-12, IFN-) may be protective. Clearly there are multiple causes of CD4 T lymphocyte apoptosis in AIDS and therapies that block or decrease that death could have significant clinical benefit.

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2003-07-01
2019-12-11
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References

  1. Adachi, Y., Oyaizu, N., Than, S., McCloskey, T. W. & Pahwa, S. ( 1996; ). IL-2 rescues in vitro lymphocyte apoptosis in patients with HIV infection: correlation with its ability to block culture-induced down-modulation of Bcl-2. J Immunol 157, 4184–4193.
    [Google Scholar]
  2. Akari, H., Bour, S., Kao, S., Adachi, A. & Strebel, K. ( 2001; ). The human immunodeficiency virus type 1 accessory protein Vpu induces apoptosis by suppressing the nuclear factor κB-dependent expression of antiapoptotic factors. J Exp Med 194, 1299–1311.[CrossRef]
    [Google Scholar]
  3. Akbar, A. N., Salmon, M. & Janossy, G. ( 1994; ). Role of bcl-2 and apoptosis in viral infections. Int Arch Allergy Immunol 105, 359–362.[CrossRef]
    [Google Scholar]
  4. Alam, A., Cohen, L. Y., Aouad, S. & Sekaly, R. P. ( 1999; ). Early activation of caspases during T lymphocyte stimulation results in selective substrate cleavage in nonapoptotic cells. J Exp Med 190, 1879–1890.[CrossRef]
    [Google Scholar]
  5. Algeciras, A., Dockrell, D. H., Lynch, D. H. & Paya, C. V. ( 1998; ). CD4 regulates susceptibility to Fas ligand- and tumor necrosis factor-mediated apoptosis. J Exp Med 187, 711–720.[CrossRef]
    [Google Scholar]
  6. Algeciras-Schimnich, A., Vlahakis, S. R., Villasis-Keever, A., Gomez, T., Heppelmann, C. J., Bou, G. & Paya, C. V. ( 2002; ). CCR5 mediates Fas- and caspase-8 dependent apoptosis of both uninfected and HIV infected primary human CD4 T cells. AIDS 16, 1467–1478.[CrossRef]
    [Google Scholar]
  7. Alimonti, J. B., Shi, L., Baijal, P. K. & Greenberg, A. H. ( 2001; ). Granzyme B induces BID-mediated cytochrome c release and mitochondrial permeability transition. J Biol Chem 276, 6974–6982.[CrossRef]
    [Google Scholar]
  8. Aries, S. P., Schaaf, B., Muller, C., Dennin, R. H. & Dalhoff, K. ( 1995; ). Fas (CD95) expression on CD4+ T cells from HIV-infected patients increases with disease progression. J Mol Med 73, 591–593.
    [Google Scholar]
  9. Arthos, J., Cicala, C., Selig, S. M. & 10 other authors ( 2002; ). The role of the CD4 receptor versus HIV coreceptors in envelope-mediated apoptosis in peripheral blood mononuclear cells. Virology 292, 98–106.[CrossRef]
    [Google Scholar]
  10. 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.[CrossRef]
    [Google Scholar]
  11. Badley, A. D., Dockrell, D. H., Algeciras, A. & 10 other authors ( 1998; ). In vivo analysis of Fas/FasL interactions in HIV-infected patients. J Clin Invest 102, 79–87.[CrossRef]
    [Google Scholar]
  12. Badley, A. D., Parato, K., Cameron, D. W. & 7 other authors ( 1999; ). Dynamic correlation of apoptosis and immune activation during treatment of HIV infection. Cell Death Differ 6, 420–432.[CrossRef]
    [Google Scholar]
  13. Banda, N. K., Bernier, J., Kurahara, D. K., Kurrle, R., Haigwood, N., Sekaly, R. P. & Finkel, T. H. ( 1992; ). Crosslinking CD4 by human immunodeficiency virus gp120 primes T cells for activation-induced apoptosis. J Exp Med 176, 1099–1106.[CrossRef]
    [Google Scholar]
  14. Bartz, S. R. & Emerman, M. ( 1999; ). Human immunodeficiency virus type 1 Tat induces apoptosis and increases sensitivity to apoptotic signals by up-regulating FLICE/caspase-8. J Virol 73, 1956–1963.
    [Google Scholar]
  15. Baumler, C. B., Bohler, T., Herr, I., Benner, A., Krammer, P. H. & Debatin, K. M. ( 1996; ). Activation of the CD95 (APO-1/Fas) system in T cells from human immunodeficiency virus type-1-infected children. Blood 88, 1741–1746.
    [Google Scholar]
  16. Blanco, J., Barretina, J., Ferri, K. F. & 7 other authors ( 2003; ). Cell-surface-expressed HIV-1 envelope induces the death of CD4 T cells during GP41-mediated hemifusion-like events. Virology 305, 318–329.[CrossRef]
    [Google Scholar]
  17. Borthwick, N. J., Lowdell, M., Salmon, M. & Akbar, A. N. ( 2000; ). Loss of CD28 expression on CD8+ T cells is induced by IL-2 receptor gamma chain signalling cytokines and type I IFN, and increases susceptibility to activation-induced apoptosis. Int Immunol 12, 1005–1013.[CrossRef]
    [Google Scholar]
  18. Bretscher, P. A. ( 1999; ). A two-step, two-signal model for the primary activation of precursor helper T cells. Proc Natl Acad Sci U S A 96, 185–190.[CrossRef]
    [Google Scholar]
  19. Budihardjo, I., Oliver, H., Lutter, M., Luo, X. & Wang, X. ( 1999; ). Biochemical pathways of caspase activation during apoptosis. Annu Rev Cell Dev Biol 15, 269–290.[CrossRef]
    [Google Scholar]
  20. Capobianchi, M. R. ( 1996; ). Induction of lymphomonocyte activation by HIV-1 glycoprotein gp120. Possible role in AIDS pathogenesis. J Biol Regul Homeost Agents 10, 83–91.
    [Google Scholar]
  21. Casella, C. R., Rapaport, E. L. & Finkel, T. H. ( 1999; ). Vpu increases susceptibility of human immunodeficiency virus type 1-infected cells to fas killing. J Virol 73, 92–100.
    [Google Scholar]
  22. Chang, H. C., Samaniego, F., Nair, B. C., Buonaguro, L. & Ensoli, B. ( 1997; ). HIV-1 Tat protein exits from cells via a leaderless secretory pathway and binds to extracellular matrix-associated heparan sulfate proteoglycans through its basic region. AIDS 11, 1421–1431.[CrossRef]
    [Google Scholar]
  23. Chen, D., Wang, M., Zhou, S. & Zhou, Q. ( 2002; ). HIV-1 Tat targets microtubules to induce apoptosis, a process promoted by the pro-apoptotic Bcl-2 relative Bim. EMBO J 21, 6801–6810.[CrossRef]
    [Google Scholar]
  24. Chougnet, C., Thomas, E., Landay, A. L., Kessler, H. A., Buchbinder, S., Scheer, S. & Shearer, G. M. ( 1998; ). CD40 ligand and IFN-γ synergistically restore IL-12 production in HIV-infected patients. Eur J Immunol 28, 646–656.[CrossRef]
    [Google Scholar]
  25. Cicala, C., Arthos, J., Ruiz, M., Vaccarezza, M., Rubbert, A., Riva, A., Wildt, K., Cohen, O. & Fauci, A. S. ( 1999; ). Induction of phosphorylation and intracellular association of CC chemokine receptor 5 and focal adhesion kinase in primary human CD4+ T cells by macrophage-tropic HIV envelope. J Immunol 163, 420–426.
    [Google Scholar]
  26. Cicala, C., Arthos, J., Rubbert, A., Selig, S., Wildt, K., Cohen, O. J. & Fauci, A. S. ( 2000; ). HIV-1 envelope induces activation of caspase-3 and cleavage of focal adhesion kinase in primary human CD4+ T cells. Proc Natl Acad Sci U S A 97, 1178–1183.[CrossRef]
    [Google Scholar]
  27. Clark, S. J., Saag, M. S., Decker, W. D., Campbell-Hill, S., Roberson, J. L., Veldkamp, P. J., Kappes, J. C., Hahn, B. H. & Shaw, G. M. ( 1991; ). High titers of cytopathic virus in plasma of patients with symptomatic primary HIV-1 infection. New Engl J Med 324, 954–960.[CrossRef]
    [Google Scholar]
  28. Clerici, M. & Shearer, G. M. ( 1994; ). The Th1-Th2 hypothesis of HIV infection: new insights. Immunol Today 15, 575–581.[CrossRef]
    [Google Scholar]
  29. Clerici, M., Sarin, A., Berzofsky, J. A. & 10 other authors ( 1996; ). Antigen-stimulated apoptotic T-cell death in HIV infection is selective for CD4+ T cells, modulated by cytokines and effected by lymphotoxin. AIDS 10, 603–611.[CrossRef]
    [Google Scholar]
  30. Cohen, P. L. & Eisenberg, R. A. ( 1992; ). The lpr and gld genes in systemic autoimmunity: life and death in the Fas lane. Immunol Today 13, 427–428.[CrossRef]
    [Google Scholar]
  31. Conti, L., Rainaldi, G., Matarrese, P. & 7 other authors ( 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.[CrossRef]
    [Google Scholar]
  32. Copeland, K. F. & Heeney, J. L. ( 1996; ). T helper cell activation and human retroviral pathogenesis. Microbiol Rev 60, 722–742.
    [Google Scholar]
  33. Crise, B., Buonocore, L. & Rose, J. K. ( 1990; ). CD4 is retained in the endoplasmic reticulum by the human immunodeficiency virus type 1 glycoprotein precursor. J Virol 64, 5585–5593.
    [Google Scholar]
  34. Daar, E. S., Moudgil, T., Meyer, R. D. & Ho, D. D. ( 1991; ). Transient high levels of viremia in patients with primary human immunodeficiency virus type 1 infection. New Engl J Med 324, 961–964.[CrossRef]
    [Google Scholar]
  35. Dockrell, D. H., Badley, A. D., Algeciras-Schimnich, A., Simpson, M., Schut, R., Lynch, D. H. & Paya, C. V. ( 1999; ). Activation-induced CD4+ T cell death in HIV-positive individuals correlates with Fas susceptibility, CD4+ T cell count, and HIV plasma viral copy number. AIDS Res Hum Retroviruses 15, 1509–1518.[CrossRef]
    [Google Scholar]
  36. Embretson, J., Zupancic, M., Ribas, J. L., Burke, A., Racz, P., Tenner-Racz, K. & Haase, A. T. ( 1993; ). Massive covert infection of helper T lymphocytes and macrophages by HIV during the incubation period of AIDS. Nature 362, 359–362.[CrossRef]
    [Google Scholar]
  37. Ensoli, B., Barillari, G., Salahuddin, S. Z., Gallo, R. C. & Wong-Staal, F. ( 1990; ). Tat protein of HIV-1 stimulates growth of cells derived from Kaposi's sarcoma lesions of AIDS patients. Nature 345, 84–86.[CrossRef]
    [Google Scholar]
  38. Esser, M. T., Bess, J. W., Jr, Suryanarayana, K., Chertova, E., Marti, D., Carrington, M., Arthur, L. O. & Lifson, J. D. ( 2001; ). Partial activation and induction of apoptosis in CD4+ and CD8+ T lymphocytes by conformationally authentic noninfectious human immunodeficiency virus type 1. J Virol 75, 1152–1164.[CrossRef]
    [Google Scholar]
  39. Estaquier, J., Idziorek, T., Zou, W., Emilie, D., Farber, C. M., Bourez, J. M. & Ameisen, J. C. ( 1995; ). T helper type 1/T helper type 2 cytokines and T cell death: preventive effect of interleukin 12 on activation-induced and CD95 (FAS/APO-1)-mediated apoptosis of CD4+ T cells from human immunodeficiency virus-infected persons. J Exp Med 182, 1759–1767.[CrossRef]
    [Google Scholar]
  40. Estaquier, J., Tanaka, M., Suda, T., Nagata, S., Golstein, P. & Ameisen, J. C. ( 1996; ). Fas-mediated apoptosis of CD4+ and CD8+ T cells from human immunodeficiency virus-infected persons: differential in vitro preventive effect of cytokines and protease antagonists. Blood 87, 4959–4966.
    [Google Scholar]
  41. Evan, G. & Littlewood, T. ( 1998; ). A matter of life and cell death. Science 281, 1317–1322.[CrossRef]
    [Google Scholar]
  42. Everett, H. & McFadden, G. ( 1999; ). Apoptosis: an innate immune response to virus infection. Trends Microbiol 7, 160–165.[CrossRef]
    [Google Scholar]
  43. Fauci, A. S. ( 1988; ). The human immunodeficiency virus: infectivity and mechanisms of pathogenesis. Science 239, 617–622.[CrossRef]
    [Google Scholar]
  44. Finkel, T. H., Tudor-Williams, G., Banda, N. K., Cotton, M. F., Curiel, T., Monks, C., Baba, T. W., Ruprecht, R. M. & Kupfer, A. ( 1995; ). Apoptosis occurs predominantly in bystander cells and not in productively infected cells of HIV- and SIV-infected lymph nodes. Nat Med 1, 129–134.[CrossRef]
    [Google Scholar]
  45. Fowke, K. R., D'Amico, R., Chernoff, D. N., Pottage, J. C., Jr, Benson, C. A., Sha, B. E., Kessler, H. A., Landay, A. L. & Shearer, G. M. ( 1997; ). Immunologic and virologic evaluation after influenza vaccination of HIV- 1-infected patients. AIDS 11, 1013–1021.[CrossRef]
    [Google Scholar]
  46. Fowke, K. R., Kaul, R., Rosenthal, K. L. & 9 other authors ( 2000; ). HIV-1-specific cellular immune responses among HIV-1-resistant sex workers. Immunol Cell Biol 78, 586–595.[CrossRef]
    [Google Scholar]
  47. Furtado, M. R., Kingsley, L. A. & Wolinsky, S. M. ( 1995; ). Changes in the viral mRNA expression pattern correlate with a rapid rate of CD4+ T-cell number decline in human immunodeficiency virus type 1-infected individuals. J Virol 69, 2092–2100.
    [Google Scholar]
  48. Galli, G., Annunziato, F., Cosmi, L., Manetti, R., Maggi, E. & Romagnani, S. ( 2001; ). Th1 and th2 responses, HIV-1 coreceptors and HIV-1 infection. J Biol Regul Homeost Agents 15, 308–313.
    [Google Scholar]
  49. Gibellini, D., Re, M. C., Ponti, C., Maldini, C., Celeghini, C., Cappellini, A., La Placa, M. & Zauli, G. ( 2001; ). HIV-1 Tat protects CD4+ Jurkat T lymphoblastoid cells from apoptosis mediated by TNF-related apoptosis-inducing ligand. Cell Immunol 207, 89–99.[CrossRef]
    [Google Scholar]
  50. Giri, J. G., Anderson, D. M., Kumaki, S., Park, L. S., Grabstein, K. H. & Cosman, D. ( 1995; ). IL-15, a novel T cell growth factor that shares activities and receptor components with IL-2. J Leukoc Biol 57, 763–766.
    [Google Scholar]
  51. Golstein, P. ( 1998; ). Cell death in us and others. Science 281, 1283.[CrossRef]
    [Google Scholar]
  52. Gonzalez, M. E. & Carrasco, L. ( 2001; ). Human immunodeficiency virus type 1 VPU protein affects Sindbis virus glycoprotein processing and enhances membrane permeabilization. Virology 279, 201–209.[CrossRef]
    [Google Scholar]
  53. Gougeon, M. L. & Montagnier, L. ( 1993; ). Apoptosis in AIDS. Science 260, 1269–1270.[CrossRef]
    [Google Scholar]
  54. Gougeon, M. L., Lecoeur, H., Dulioust, A., Enouf, M. G., Crouvoiser, M., Goujard, C., Debord, T. & Montagnier, L. ( 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.
    [Google Scholar]
  55. Gross, A. ( 2001; ). BCL-2 proteins: regulators of the mitochondrial apoptotic program. IUBMB Life 52, 231–236.[CrossRef]
    [Google Scholar]
  56. Gummuluru, S. & Emerman, M. ( 1999; ). Cell cycle- and Vpr-mediated regulation of human immunodeficiency virus type 1 expression in primary and transformed T-cell lines. J Virol 73, 5422–5430.
    [Google Scholar]
  57. Han, X., Becker, K., Degen, H. J., Jablonowski, H. & Strohmeyer, G. ( 1996; ). Synergistic stimulatory effects of tumour necrosis factor α and interferon γ on replication of human immunodeficiency virus type 1 and on apoptosis of HIV-1-infected host cells. Eur J Clin Invest 26, 286–292.[CrossRef]
    [Google Scholar]
  58. Hanabuchi, S., Koyanagi, M., Kawasaki, A. & 7 other authors ( 1994; ). Fas and its ligand in a general mechanism of T-cell-mediated cytotoxicity. Proc Natl Acad Sci U S A 91, 4930–4934.[CrossRef]
    [Google Scholar]
  59. Ho, D. D., Neumann, A. U., Perelson, A. S., Chen, W., Leonard, J. M. & Markowitz, M. ( 1995; ). Rapid turnover of plasma virions and CD4 lymphocytes in HIV-1 infection. Nature 373, 123–126.[CrossRef]
    [Google Scholar]
  60. Hober, D., Benyoucef, S., Delannoy, A. S., de Groote, D., Ajana, F., Mouton, Y. & Wattre, P. ( 1996; ). High plasma level of soluble tumor necrosis factor receptor type II (sTNFRII) in asymptomatic HIV-1-infected patients. Infection 24, 213–217.[CrossRef]
    [Google Scholar]
  61. Hogan, C. M. & Hammer, S. M. ( 2001a; ). Host determinants in HIV infection and disease. Part 1: cellular and humoral immune responses. Ann Intern Med 134, 761–776.[CrossRef]
    [Google Scholar]
  62. Hogan, C. M. & Hammer, S. M. ( 2001b; ). Host determinants in HIV infection and disease. Part 2: genetic factors and implications for antiretroviral therapeutics. Ann Intern Med 134, 978–996.[CrossRef]
    [Google Scholar]
  63. Howcroft, T. K., Strebel, K., Martin, M. A. & Singer, D. S. ( 1993; ). Repression of MHC class I gene promoter activity by two-exon Tat of HIV. Science 260, 1320–1322.[CrossRef]
    [Google Scholar]
  64. Irmler, M., Thome, M., Hahne, M. & 10 other authors ( 1997; ). Inhibition of death receptor signals by cellular FLIP. Nature 388, 190–195.[CrossRef]
    [Google Scholar]
  65. Jacotot, E., Ferri, K. F., El Hamel, C. & 17 other authors ( 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.[CrossRef]
    [Google Scholar]
  66. Kabelitz, D., Pohl, T. & Pechhold, K. ( 1995; ). T cell apoptosis triggered via the CD3/T cell receptor complex and alternative activation pathways. Curr Top Microbiol Immunol 200, 1–14.
    [Google Scholar]
  67. Kalams, S. A., Buchbinder, S. P., Rosenberg, E. S., Billingsley, J. M., Colbert, D. S., Jones, N. G., Shea, A. K., Trocha, A. K. & Walker, B. D. ( 1999; ). Association between virus-specific cytotoxic T-lymphocyte and helper responses in human immunodeficiency virus type 1 infection. J Virol 73, 6715–6720.
    [Google Scholar]
  68. Kammerer, R., Iten, A., Frei, P. C. & Burgisser, P. ( 1996; ). Expansion of T cells negative for CD28 expression in HIV infection. Relation to activation markers and cell adhesion molecules, and correlation with prognostic markers. Med Microbiol Immunol (Berl) 185, 19–25.[CrossRef]
    [Google Scholar]
  69. Kasaian, M. T., Leite-Morris, K. A. & Biron, C. A. ( 1991; ). The role of CD4+ cells in sustaining lymphocyte proliferation during lymphocytic choriomeningitis virus infection. J Immunol 146, 1955–1963.
    [Google Scholar]
  70. Kennedy, N. J., Kataoka, T., Tschopp, J. & Budd, R. C. ( 1999; ). Caspase activation is required for T cell proliferation. J Exp Med 190, 1891–1896.[CrossRef]
    [Google Scholar]
  71. Kimata, J. T., Kuller, L., Anderson, D. B., Dailey, P. & Overbaugh, J. ( 1999; ). Emerging cytopathic and antigenic simian immunodeficiency virus variants influence AIDS progression. Nat Med 5, 535–541.[CrossRef]
    [Google Scholar]
  72. Kinter, A., Catanzaro, A., Monaco, J. & 12 other authors ( 1998; ). CC-chemokines enhance the replication of T-tropic strains of HIV-1 in CD4+ T cells: role of signal transduction. Proc Natl Acad Sci U S A 95, 11880–11885.[CrossRef]
    [Google Scholar]
  73. Koenig, S., Conley, A. J., Brewah, Y. A. & other authors ( 1995; ). Transfer of HIV-1-specific cytotoxic T lymphocytes to an AIDS patient leads to selection for mutant HIV variants and subsequent disease progression. Nat Med 1, 330–336.[CrossRef]
    [Google Scholar]
  74. Korant, B. D., Strack, P., Frey, M. W. & Rizzo, C. J. ( 1998; ). A cellular anti-apoptosis protein is cleaved by the HIV-1 protease. Adv Exp Med Biol 436, 27–29.
    [Google Scholar]
  75. Korsmeyer, S. J., Wei, M. C., Saito, M., Weiler, S., Oh, K. J. & Schlesinger, P. H. ( 2000; ). Pro-apoptotic cascade activates BID, which oligomerizes BAK or BAX into pores that result in the release of cytochrome c. Cell Death Differ 7, 1166–1173.[CrossRef]
    [Google Scholar]
  76. Kovacs, J. A., Vogel, S., Metcalf, J. A. & 14 other authors ( 2001; ). Interleukin-2 induced immune effects in human immunodeficiency virus-infected patients receiving intermittent interleukin-2 immunotherapy. Eur J Immunol 31, 1351–1360.[CrossRef]
    [Google Scholar]
  77. Ledru, E., Lecoeur, H., Garcia, S., Debord, T. & Gougeon, M. L. ( 1998; ). Differential susceptibility to activation-induced apoptosis among peripheral Th1 subsets: correlation with Bcl-2 expression and consequences for AIDS pathogenesis. J Immunol 160, 3194–3206.
    [Google Scholar]
  78. Lehmann, J. & Alber, G. ( 1998; ). Murine leishmaniosis: a paradigm for the importance of T helper 1 and T helper 2 cells. Rev Sci Tech 17, 176–187.
    [Google Scholar]
  79. Lehmann-Grube, F., Lohler, J., Utermohlen, O. & Gegin, C. ( 1993; ). Antiviral immune responses of lymphocytic choriomeningitis virus-infected mice lacking CD8+ T lymphocytes because of disruption of the beta 2-microglobulin gene. J Virol 67, 332–339.
    [Google Scholar]
  80. Lenardo, M., Chan, K. M., Hornung, F., McFarland, H., Siegel, R., Wang, J. & Zheng, L. ( 1999; ). Mature T lymphocyte apoptosis – immune regulation in a dynamic and unpredictable antigenic environment. Annu Rev Immunol 17, 221–253.[CrossRef]
    [Google Scholar]
  81. Levy, J. A. ( 1993; ). Pathogenesis of human immunodeficiency virus infection. Microbiol Rev 57, 183–289.
    [Google Scholar]
  82. Li, C. J., Friedman, D. J., Wang, C., Metelev, V. & Pardee, A. B. ( 1995; ). Induction of apoptosis in uninfected lymphocytes by HIV-1 Tat protein. Science 268, 429–431.[CrossRef]
    [Google Scholar]
  83. Li-Weber, M., Laur, O., Dern, K. & Krammer, P. H. ( 2000; ). T cell activation-induced and HIV tat-enhanced CD95(APO-1/Fas) ligand transcription involves NF-κB. Eur J Immunol 30, 661–670.[CrossRef]
    [Google Scholar]
  84. Los, M., Wesselborg, S. & Schulze-Osthoff, K. ( 1999; ). The role of caspases in development, immunity and apoptotic signal transduction: lessons from knockout mice. Immunity 10, 629–639.[CrossRef]
    [Google Scholar]
  85. Lukacher, A. E., Braciale, V. L. & Braciale, T. J. ( 1984; ). In vivo effector function of influenza virus-specific cytotoxic T lymphocyte clones is highly specific. J Exp Med 160, 814–826.[CrossRef]
    [Google Scholar]
  86. Macaubas, C., Sly, P. D., Burton, P. & 7 other authors ( 1999; ). Regulation of T-helper cell responses to inhalant allergen during early childhood. Clin Exp Allergy 29, 1223–1231.[CrossRef]
    [Google Scholar]
  87. Maloy, K. J., Burkhart, C., Junt, T. M., Odermatt, B., Oxenius, A., Piali, L., Zinkernagel, R. M. & Hengartner, H. ( 2000; ). CD4+ T cell subsets during virus infection. Protective capacity depends on effector cytokine secretion and on migratory capability. J Exp Med 191, 2159–2170.[CrossRef]
    [Google Scholar]
  88. Mann, D. A. & Frankel, A. D. ( 1991; ). Endocytosis and targeting of exogenous HIV-1 Tat protein. EMBO J 10, 1733–1739.
    [Google Scholar]
  89. Marschner, S., Hunig, T., Cambier, J. C. & Finkel, T. H. ( 2002; ). Ligation of human CD4 interferes with antigen-induced activation of primary T cells. Immunol Lett 82, 131–139.[CrossRef]
    [Google Scholar]
  90. Matloubian, M., Concepcion, R. J. & Ahmed, R. ( 1994; ). CD4+ T cells are required to sustain CD8+ cytotoxic T-cell responses during chronic viral infection. J Virol 68, 8056–8063.
    [Google Scholar]
  91. Murray, R. J., Kurilla, M. G., Brooks, J. M., Thomas, W. A., Rowe, M., Kieff, E. & Rickinson, A. B. ( 1992; ). Identification of target antigens for the human cytotoxic T cell response to Epstein–Barr virus (EBV): implications for the immune control of EBV-positive malignancies. J Exp Med 176, 157–168.[CrossRef]
    [Google Scholar]
  92. Nagata, S. & Suda, T. ( 1995; ). Fas and Fas ligand: lpr and gld mutations. Immunol Today 16, 39–43.[CrossRef]
    [Google Scholar]
  93. Naora, H. & Gougeon, M. L. ( 1999; ). Interleukin-15 is a potent survival factor in the prevention of spontaneous but not CD95-induced apoptosis in CD4 and CD8 T lymphocytes of HIV-infected individuals. Correlation with its ability to increase BCL-2 expression. Cell Death Differ 6, 1002–1011.[CrossRef]
    [Google Scholar]
  94. New, D. R., Ma, M., Epstein, L. G., Nath, A. & Gelbard, H. A. ( 1997; ). Human immunodeficiency virus type 1 Tat protein induces death by apoptosis in primary human neuron cultures. J Neurovirol 3, 168–173.[CrossRef]
    [Google Scholar]
  95. Nie, Z., Phenix, B. N., Lum, J. J., Alam, A., Lynch, D. H., Beckett, B., Krammer, P. H., Sekaly, R. P. & Badley, A. D. ( 2002; ). HIV-1 protease processes procaspase 8 to cause mitochondrial release of cytochrome c, caspase cleavage and nuclear fragmentation. Cell Death Differ 9, 1172–1184.[CrossRef]
    [Google Scholar]
  96. Nishimura, Y., Hosokawa, T., Hosono, M., Baba, M. & Hosokawa, M. ( 2002; ). Insufficient interleukin-2 production from splenic CD4+ T cells causes impaired cell proliferation and early apoptosis in SAMP1, a strain of senescence-accelerated mouse. Immunology 107, 190–198.[CrossRef]
    [Google Scholar]
  97. O'Flaherty, E., Wong, W. K., Pettit, S. J., Seymour, K., Ali, S. & Kirby, J. A. ( 2000; ). Regulation of T-cell apoptosis: a mixed lymphocyte reaction model. Immunology 100, 289–299.[CrossRef]
    [Google Scholar]
  98. Ohmi, Y., Shiku, H. & Nishimura, T. ( 1999; ). Tumor-specific targeting of T helper type 1 (Th1) cells by anti-CD3 x anti-c-ErbB-2 bispecific antibody. Cancer Immunol Immunother 48, 456–462.[CrossRef]
    [Google Scholar]
  99. Okada, H., Takei, R. & Tashiro, M. ( 1997; ). HIV-1 Nef protein-induced apoptotic cytolysis of a broad spectrum of uninfected human blood cells independently of CD95(Fas). FEBS Lett 414, 603–606.[CrossRef]
    [Google Scholar]
  100. Okada, H., Morikawa, S. & Tashiro, M. ( 1998; ). HIV-1 Nef binding protein expressed on the surface of murine blood cells. Med Microbiol Immunol (Berl) 186, 201–207.[CrossRef]
    [Google Scholar]
  101. Oyaizu, N., McCloskey, T. W., Than, S., Hu, R., Kalyanaraman, V. S. & Pahwa, S. ( 1994; ). Cross-linking of CD4 molecules upregulates Fas antigen expression in lymphocytes by inducing interferon-gamma and tumor necrosis factor-α secretion. Blood 84, 2622–2631.
    [Google Scholar]
  102. Perelson, A. S., Neumann, A. U., Markowitz, M., Leonard, J. M. & Ho, D. D. ( 1996; ). HIV-1 dynamics in vivo: virion clearance rate, infected cell life-span, and viral generation time. Science 271, 1582–1586.[CrossRef]
    [Google Scholar]
  103. Phenix, B. N. & Badley, A. D. ( 2002; ). Influence of mitochondrial control of apoptosis on the pathogenesis, complications and treatment of HIV infection. Biochimie 84, 251–264.[CrossRef]
    [Google Scholar]
  104. Piatak, M., Jr, Saag, M. S., Yang, L. C., Clark, S. J., Kappes, J. C., Luk, K. C., Hahn, B. H., Shaw, G. M. & Lifson, J. D. ( 1993; ). High levels of HIV-1 in plasma during all stages of infection determined by competitive PCR. Science 259, 1749–1754.[CrossRef]
    [Google Scholar]
  105. Pugliese, A., Cantamessa, C., Saini, A., Piragino, A., Gennero, L., Martini, C. & Torre, D. ( 1999; ). Effects of the exogenous Nef protein on HIV-1 target cells. Cell Biochem Funct 17, 183–192.[CrossRef]
    [Google Scholar]
  106. Re, M., Gibellini, D., Aschbacher, R., Vignoli, M., Furlini, G., Ramazzotti, E., Bertolaso, L. & La Placa, M. ( 1998; ). High levels of HIV-1 replication show a clear correlation with downmodulation of Bcl-2 protein in peripheral blood lymphocytes of HIV-1-seropositive subjects. J Med Virol 56, 66–73.[CrossRef]
    [Google Scholar]
  107. Richman, D. D. & Bozzette, S. A. ( 1994; ). The impact of the syncytium-inducing phenotype of human immunodeficiency virus on disease progression. J Infect Dis 169, 968–974.[CrossRef]
    [Google Scholar]
  108. Robinson, D. S., Hamid, Q., Jacobson, M., Ying, S., Kay, A. B. & Durham, S. R. ( 1993; ). Evidence for Th2-type T helper cell control of allergic disease in vivo. Springer Semin Immunopathol 15, 17–27.
    [Google Scholar]
  109. Rosenberg, E. S. & Walker, B. D. ( 1998; ). HIV type 1-specific helper T cells: a critical host defense. AIDS Res Hum Retroviruses 14 (Suppl. 2), S143–147.
    [Google Scholar]
  110. Rosenberg, E. S., Billingsley, J. M., Caliendo, A. M., Boswell, S. L., Sax, P. E., Kalams, S. A. & Walker, B. D. ( 1997; ). Vigorous HIV-1-specific CD4+ T cell responses associated with control of viremia. Science 278, 1447–1450.[CrossRef]
    [Google Scholar]
  111. Roumier, T., Vieira, H. L., Castedo, M. & 8 other authors ( 2002; ). The C-terminal moiety of HIV-1 Vpr induces cell death via a caspase-independent mitochondrial pathway. Cell Death Differ 9, 1212–1219.[CrossRef]
    [Google Scholar]
  112. Saha, K., Bentsman, G., Chess, L. & Volsky, D. J. ( 1998; ). Endogenous production of β-chemokines by CD4+, but not CD8+, T-cell clones correlates with the clinical state of human immunodeficiency virus type 1 (HIV-1)-infected individuals and may be responsible for blocking infection with non-syncytium-inducing HIV-1 in vitro. J Virol 72, 876–881.
    [Google Scholar]
  113. Salghetti, S., Mariani, R. & Skowronski, J. ( 1995; ). Human immunodeficiency virus type 1 Nef and p56lck protein-tyrosine kinase interact with a common element in CD4 cytoplasmic tail. Proc Natl Acad Sci U S A 92, 349–353.[CrossRef]
    [Google Scholar]
  114. Sastry, K. J., Marin, M. C., Nehete, P. N., McConnell, K., el-Naggar, A. K. & McDonnell, T. J. ( 1996; ). Expression of human immunodeficiency virus type I tat results in down-regulation of bcl-2 and induction of apoptosis in hematopoietic cells. Oncogene 13, 487–493.
    [Google Scholar]
  115. Schirren, C. A., Jung, M., Worzfeld, T. & 7 other authors ( 2000; ). Cytokine profile of liver- and blood-derived nonspecific T cells after liver transplantation: T helper cells type 1/0 lymphokines dominate in recurrent hepatitis C virus infection and rejection. Liver Transpl 6, 222–228.[CrossRef]
    [Google Scholar]
  116. Schwartz, O., Marechal, V., Le Gall, S., Lemonnier, F. & Heard, J. M. ( 1996; ). Endocytosis of major histocompatibility complex class I molecules is induced by the HIV-1 Nef protein. Nat Med 2, 338–342.[CrossRef]
    [Google Scholar]
  117. Shaw, G. M., Hahn, B. H., Arya, S. K., Groopman, J. E., Gallo, R. C. & Wong-Staal, F. ( 1984; ). Molecular characterization of human T-cell leukemia (lymphotropic) virus type III in the acquired immune deficiency syndrome. Science 226, 1165–1171.[CrossRef]
    [Google Scholar]
  118. Silvestris, F., Cafforio, P., Frassanito, M. A., Tucci, M., Romito, A., Nagata, S. & Dammacco, F. ( 1996; ). Overexpression of Fas antigen on T cells in advanced HIV-1 infection: differential ligation constantly induces apoptosis. AIDS 10, 131–141.[CrossRef]
    [Google Scholar]
  119. Silvestris, F., Camarda, G., Del Prete, A., Tucci, M. & Dammacco, F. ( 1999; ). Nef protein induces differential effects in CD8+ cells from HIV-1- infected patients. Eur J Clin Invest 29, 980–991.[CrossRef]
    [Google Scholar]
  120. Somma, F., Tuosto, L., Montani, M. S., Di Somma, M. M., Cundari, E. & Piccolella, E. ( 2000; ). Engagement of CD4 before TCR triggering regulates both Bax- and Fas (CD95)-mediated apoptosis. J Immunol 164, 5078–5087.[CrossRef]
    [Google Scholar]
  121. Sousa, A. E., Chaves, A. F., Doroana, M., Antunes, F. & Victorino, R. M. ( 1999; ). Early reduction of the over-expression of CD40L, OX40 and Fas on T cells in HIV-1 infection during triple anti-retroviral therapy: possible implications for lymphocyte traffic and functional recovery. Clin Exp Immunol 116, 307–315.[CrossRef]
    [Google Scholar]
  122. Srivastava, R. K., Sasaki, C. Y., Hardwick, J. M. & Longo, D. L. ( 1999; ). Bcl-2-mediated drug resistance: inhibition of apoptosis by blocking nuclear factor of activated T lymphocytes (NFAT)-induced Fas ligand transcription. J Exp Med 190, 253–265.[CrossRef]
    [Google Scholar]
  123. Strack, P. R., Frey, M. W., Rizzo, C. J. & 7 other authors ( 1996; ). Apoptosis mediated by HIV protease is preceded by cleavage of Bcl-2. Proc Natl Acad Sci U S A 93, 9571–9576.[CrossRef]
    [Google Scholar]
  124. Strasser, A., O'Connor, L. & Dixit, V. M. ( 2000; ). Apoptosis signaling. Annu Rev Biochem 69, 217–245.[CrossRef]
    [Google Scholar]
  125. Stylianou, E., Yndestad, A., Sikkeland, L. I., Bjerkeli, V., Damas, J. K., Haug, T., Eiken, H. G., Aukrust, P. & Froland, S. S. ( 2002; ). Effects of interferon-α on gene expression of chemokines and members of the tumour necrosis factor superfamily in HIV-infected patients. Clin Exp Immunol 130, 279–285.[CrossRef]
    [Google Scholar]
  126. Suda, T., Okazaki, T., Naito, Y., Yokota, T., Arai, N., Ozaki, S., Nakao, K. & Nagata, S. ( 1995; ). Expression of the Fas ligand in cells of T cell lineage. J Immunol 154, 3806–3813.
    [Google Scholar]
  127. Sylwester, A., Murphy, S., Shutt, D. & Soll, D. R. ( 1997; ). HIV-induced T cell syncytia are self-perpetuating and the primary cause of T cell death in culture. J Immunol 158, 3996–4007.
    [Google Scholar]
  128. Tateyama, M., Oyaizu, N., McCloskey, T. W., Than, S. & Pahwa, S. ( 2000; ). CD4 T lymphocytes are primed to express Fas ligand by CD4 cross-linking and to contribute to CD8 T-cell apoptosis via Fas/FasL death signaling pathway. Blood 96, 195–202.
    [Google Scholar]
  129. Trillo-Pazos, G., McFarlane-Abdulla, E., Campbell, I. C., Pilkington, G. J. & Everall, I. P. ( 2000; ). Recombinant nef HIV-IIIB protein is toxic to human neurons in culture. Brain Res 864, 315–326.[CrossRef]
    [Google Scholar]
  130. von Herrath, M. G., Yokoyama, M., Dockter, J., Oldstone, M. B. & Whitton, J. L. ( 1996; ). CD4-deficient mice have reduced levels of memory cytotoxic T lymphocytes after immunization and show diminished resistance to subsequent virus challenge. J Virol 70, 1072–1079.
    [Google Scholar]
  131. Walker, R. E., Spooner, K. M., Kelly, G. & 10 other authors ( 1996; ). Inhibition of immunoreactive tumor necrosis factor-α by a chimeric antibody in patients infected with human immunodeficiency virus type 1. J Infect Dis 174, 63–68.[CrossRef]
    [Google Scholar]
  132. Watanabe, N., Yamaguchi, T., Akimoto, Y., Rattner, J. B., Hirano, H. & Nakauchi, H. ( 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.[CrossRef]
    [Google Scholar]
  133. Wei, X., Ghosh, S. K., Taylor, M. E. & other authors ( 1995; ). Viral dynamics in human immunodeficiency virus type 1 infection. Nature 373, 117–122.[CrossRef]
    [Google Scholar]
  134. Westendorp, M. O., Frank, R., Ochsenbauer, C., Stricker, K., Dhein, J., Walczak, H., Debatin, K. M. & Krammer, P. H. ( 1995; ). Sensitization of T cells to CD95-mediated apoptosis by HIV-1 Tat and gp120. Nature 375, 497–500.[CrossRef]
    [Google Scholar]
  135. WHO. ( 2002; ). AIDS epidemic update 2002. UNAIDS.
  136. Willey, R. L., Maldarelli, F., Martin, M. A. & Strebel, K. ( 1992; ). Human immunodeficiency virus type 1 Vpu protein induces rapid degradation of CD4. J Virol 66, 7193–7200.
    [Google Scholar]
  137. Wolf, B. B. & Green, D. R. ( 1999; ). Suicidal tendencies: apoptotic cell death by caspase family proteinases. J Biol Chem 274, 20049–20052.[CrossRef]
    [Google Scholar]
  138. Xu, X. N., Laffert, B., Screaton, G. R., Kraft, M., Wolf, D., Kolanus, W., Mongkolsapay, J., McMichael, A. J. & Baur, A. S. ( 1999; ). Induction of Fas ligand expression by HIV involves the interaction of Nef with the T cell receptor zeta chain. J Exp Med 189, 1489–1496.[CrossRef]
    [Google Scholar]
  139. Yang, Y., Dong, B., Mittelstadt, P. R., Xiao, H. & Ashwell, J. D. ( 2002; ). HIV Tat binds Egr proteins and enhances Egr-dependent transactivation of the Fas ligand promoter. J Biol Chem 277, 19482–19487.[CrossRef]
    [Google Scholar]
  140. Zagury, D., Lachgar, A., Chams, V. & 10 other authors ( 1998; ). Interferon α and Tat involvement in the immunosuppression of uninfected T cells and C-C chemokine decline in AIDS. Proc Natl Acad Sci U S A 95, 3851–3856.[CrossRef]
    [Google Scholar]
  141. Zangerle, R., Gallati, H., Sarcletti, M., Wachter, H. & Fuchs, D. ( 1994; ). Tumor necrosis factor α and soluble tumor necrosis factor receptors in individuals with human immunodeficiency virus infection. Immunol Lett 41, 229–234.[CrossRef]
    [Google Scholar]
  142. Zauli, G., Gibellini, D., Caputo, A., Bassini, A., Negrini, M., Monne, M., Mazzoni, M. & Capitani, S. ( 1995; ). The human immunodeficiency virus type-1 Tat protein upregulates Bcl-2 gene expression in Jurkat T-cell lines and primary peripheral blood mononuclear cells. Blood 86, 3823–3834.
    [Google Scholar]
  143. Zauli, G., Gibellini, D., Secchiero, P., Dutartre, H., Olive, D., Capitani, S. & Collette, Y. ( 1999; ). Human immunodeficiency virus type 1 Nef protein sensitizes CD4+ T lymphoid cells to apoptosis via functional upregulation of the CD95/CD95 ligand pathway. Blood 93, 1000–1010.
    [Google Scholar]
  144. Zeevi, A., Spichty, K., Banas, R. & 8 other authors ( 1999; ). Clinical significance of cytomegalovirus-specific T helper responses and cytokine production in lung transplant recipients. Intervirology 42, 291–300.[CrossRef]
    [Google Scholar]
  145. Zhang, M., Li, X., Pang, X., Ding, L., Wood, O., Clouse, K., Hewlett, I. & Dayton, A. I. ( 2001; ). Identification of a potential HIV-induced source of bystander-mediated apoptosis in T cells: upregulation of trail in primary human macrophages by HIV-1 tat. J Biomed Sci 8, 290–296.[CrossRef]
    [Google Scholar]
  146. Zimmermann, K. C., Bonzon, C. & Green, D. R. ( 2001; ). The machinery of programmed cell death. Pharmacol Ther 92, 57–70.[CrossRef]
    [Google Scholar]
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