CONCLUSION

Previous studies estimated that only 0.00001 to 0.01% of HIV-1 virions are infectious in vitro and in vivo. Thus, apoptosis of uninfected bystander cells may contribute to HIV-1 pathogenicity in vivo.

ACKNOWLEDGMENTS

We thank Dominique Thomasset and Aurelie Vacheret for technical and secretarial assistance.

REFERENCES

1. Gougeon, M.L., Ledru, E., Naora, H., Bocchino, M., and Lecoeur, H., HIV, cytokines and programmed cell death. A subtle interplay, Ann. N.Y. Acad. Sci., 926, 30, 2000.

2. Selliah, N. and Finkel, T.H., Biochemical mechanisms of HIV induced T cell apoptosis, Cell Death Differ., 8, 127, 2001.

3. Badley, A.D., McElhinny J.A., Leibson, PJ., Lynch, D.H., Alderson, M.R., and Paya, C.V., Upregu­lation of Fas ligand expression by human immunodeficiency virus in human macrophages mediates apoptosis of uninfected T lymphocytes, J. Virol., 70, 199, 1996.

4. Badley, A.D., Dockrell, D., Simpson, M., Schut, R., Lynch, D.H., Leibson, P., and Paya, C.V., Macrophage-dependent apoptosis of CD4+ T lymphocytes from HIV-infected individuals is mediated by FasL and tumor necrosis factor, J. Exp. Med., 185, 55, 1997.

5. Oyaizu, N., Adachi, Y., Hashimoto, F., McCloskey, T.W., Hosaka, N., Kayagaki, N., Yagita, H., and Pahwa, S., Monocytes express Fas ligand upon CD4 cross-linking and induce CD4+ T cells apoptosis: a possible mechanism of bystander cell death in HIV infection, J.

6. Cottrez, F., Manca, F., Dalgleish, A.G., Arenzana-Seisdedos, F., Capron, A., and Groux, H., Priming of human CD4+ antigen-specific T cells to undergo apoptosis by HIV-infected monocytes. A two-step mechanism involving the gp120 molecule, J. Clin. Invest., 99, 257, 1997.

7. Orlikowsky, T., Wang, Z.Q., Dudhane, A., Horowitz, H., Riethmuller, G., and Hoffmann, M., Cytotoxic monocytes in the blood of HIV type 1-infected subjects destroy targeted T cells in a CD95-dependent fashion, AIDS Res. Hum. Retroviruses, 13, 953, 1997.

8. Nardelli, B., Gonzalez, C.J., Schechter, M., and Valentine, F.T., CD4+ blood lymphocytes are rapidly killed in vitro by contact with autologous human immunodeficiency virus-infected cells, Proc. Natl. Acad. Sci. U.S.A., 92, 7312, 1995.

9. Kameoka, M., Suzuki, S., Kimura, T., Fujinaga, K., Auwanit, W., Luftig, R.B., and Ikuta, K., Exposure of resting peripheral blood T cells to HIV-1 particles generates CD25+ killer cells in a small subset, leading to induction of apoptosis in bystander cells, Int. Immunol., 9, 1453, 1997.

10. Kojima, H., Eshima, K., Takayama, H., and Sitkovsky, M.V., Leukocyte function-associated antigen- 1-dependent lysis of Fas+ (CD95+/Apo-1+) innocent bystanders by antigen-specific CD8+ CTL, J. Immunol., 159, 2728, 1997.

11. Oyaizu, N., McCloskey, T.W., Coronesi, M., Chirmule, N., Kalyanaraman, V.S., and Pahwa, S., Accelerated apoptosis in peripheral blood mononuclear cells (PBMCs) from human immunodeficiency virus type-1 infected patients and in CD4 cross-linked PBMCs from normal individuals, Blood, 82, 3392, 1993.

12. Finkel, T.H., Tudor-Williams, G., Banda, N.K., Cotton, M.F., Curiel, T., Monks, C., Baba, T.W., Ruprecht, R.M., and Kupfer, A., Apoptosis occurs predominantly in bystander cells and not in productively infected cells of HIV- and SIV-infected lymph nodes, Nat. Med., 1, 129, 1995.

13. Herbein, G., Mahlknecht, U., Batliwalla, F., Gregersen, P.K., Pappas, T., Butler, J., O'Brien, W.A., and Verdin, E., Apoptosis of CD8+ T cells is mediated by macrophages through interaction of HIV gp120 with chemokine receptor CXCR4, Nature, 395, 189, 1998.

14. Mosier, D.E., Gulizia, R.J., McIsaac, P.D., Torbett, B.E., and Levy, J.A., Rapid loss of CD4+ T cells in human-PBL-SCID mice by noncytopathic HIV isolates, Science, 260, 689, 1993.

15. Gendelman, H.E., Ehrlich, G.D., Baca, L.M., Conley, S., Ribas, J., Kalter, D.C., Meltzer, M.S., Poiesz,

B. J., and Nara, P., The inability of human immunodeficiency virus to infect chimpanzee monocytes can be overcome by serial viral passage in vivo, J. Virol., 65, 3853, 1991.

16. Schuitemaker, H., Mayaard, L., Koostra, N.A., Dubbes, R., Otto, S.A., Tersmette, M., Heeney, J.L., and Miedema, F., Lack of T cell dysfunction and programmed cell death in human immunodeficiency virus type 1-infected chimpanzees correlates with absence of monocytotropic variants, J. Infect. Dis., 168, 1140, 1993.

17. Banda, N.K., Bernier, J., Kurahara, D.K., Kurrle, R., Haigwood, N., Sekaly, R.P., and Finkel, T.H., Crosslinking CD4 by human immunodeficiency virus gp120 primes T cells for activation-induced apoptosis, J. Exp. Med., 176, 1099, 1992.

18. Lewis, D.E., Ng Tang, D.S., Wang, X., and Kozinetz, C., Costimulatory pathways mediate monocyte­dependent lymphocyte apoptosis in HIV, Clin. Immunol., 90, 302, 1999.

19. Sloand, E.M., Yound, N.S., Kumar, P., Weichold, F.F., Sato, T., and Maciejewski, J.P., Role of Fas ligand and receptor in the mechanism of T-cell depletion in acquired immunodeficiency syndrome: effect on CD4+ lymphocyte depletion and human immunodeficiency virus replication, Blood, 89, 1357, 1997.

20. Miller, M.D., Warmerdam, M.T., Page, K.A., Feinberg, M.B., and Greene, W.C., Expression of the human immunodeficiency virus type 1 (HIV-1) Nef gene during HIV-1 production increases progeny particle infectivity independently of gp160 or viral entry, J. Virol., 69, 579, 1995.

21. Mitra, D., Steiner, M., Lynch, D.H., Staiano-Coico, L., and Laurence, J., HIV-1 upregulates Fas ligand expression in CD4+ T cells in vitro and in vivo: association with Fas-mediated apoptosis and modulation by aurintricarboxylic acid, Immunology, 87, 581, 1996.

22. Silvestris, F., Camarda, G., Cafforio, P., and Dammacco, F., Upregulation of Fas ligand secretion in non-lymphopenic stages of HIV-1 infection, AIDS, 12, 1103, 1998.

23. Hosaka, N., Oyaizu, N., Kaplan, M.H., Yagita, H., and Pahwa, S., Membrane and soluble forms of Fas (CD95) and Fas ligand in peripheral blood mononuclear cells and in plasma from human immu­nodeficiency virus-infected persons, J. Infect. Dis., 178, 1030, 1998.

24. Dockrell, D.H., Badley, A.D., Villacian, J.S., Heppelmann, C.J., Algeciras, A., Ziesmer, S., Yagita, H., Lynch, D.H., Roche, P.C., Leibson, PJ., and Paya, C.V., The expression of Fas ligand by mac­rophages and its upregulation by human immunodeficiency virus infection, J. Clin. Invest., 101, 2394,

1998.

25. Orlikowsky, T.W., Wang, ZQ, Dudhane, A., Dannecker, G.E., Niethammer, D., Wormser, G.P., Hoff­mann, M.K., and Horowitz, H.W., Dexamethasone inhibits CD4 T cell deletion mediated by mac­rophages from human immunodeficiency virus-infected persons, J. Infect. Dis., 184, 1328, 2001.

26. Lum, J.J., Pilon, A.A., Sanchez-Dardon, J., Phenix, B.N., Kim, J.E., Mihowich, J., Jamison, K., Hawley- Foss, N., Lynch, D.H., and Badley, A.D., Induction of cell death in human immunodeficiency virus- infected macrophages and resting memory CD4 T cells by TRAIL/Apo2, J. Virol., 75, 11128, 2001.

27. Zheng, L., Fisher, G., Miller, R.E., Peschon, J., Lynch, D.H., and Lenardo, M.J., Induction of apoptosis in mature T cells by tumour necrosis factor, Nature, 377, 348, 1995.

28. Katsikis, P.D., Garcia-Ojeda, M.E., Torres-Roca, J.F., Tijoe, I.M., Smith, C.A., Herzenberg, L.A., and Herzenberg, L.A., Interleukin-1 converting enzyme-like protease involvement in Fas-induced and activation-induced peripheral blood T cell apoptosis in HIV infection. TNF-related apoptosis-inducing ligand can mediate activation-induced T cell death in HIV infection, J. Exp. Med., 186, 1365, 1997.

29. Jeremias, I., Herr, I., Boehler, T., and Debatin, K.M., TRAIL/Apo-2-ligand-induced apoptosis in human T cells, Eur J.

30. Zhang, M., Li, X., Pang, X., Ding, l., Wood, O., Clouse, K., Hewlett, I., and Dayton, A.I., 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, 2001.

31. Yang, Y., Tikhonov, I., Ruckwardt, T.J., Djavani, M., Zapata, J.C., Pauza, C.D., and Salvato, M.S., Monocytes treated with human immunodeficiency virus Tat kill uninfected CD4(+) cells by a tumor necrosis factor-related apoptosis-induced ligand-mediated mechanism, J. Virol., 77, 6700, 2003.

32. Berndt, C., Mopps, B., Angermuller, S., Gierschik, P., and Krammer, P.H., CXCR4 and CD4 mediate a rapid CD95-independent cell death in CD4(+) T cells, Proc. Natl. Acad. Sci. U.S.A., 95, 12556, 1998.

33. Holm, G.H., Zhang, C., Gorry, P.R., Peden, K., Schols, D., De Clercq, E., and Gabuzda, D., Apoptosis of bystander T cells induced by human immunodeficiency virus type 1 with increased envelope/recep- tor affinity and coreceptor binding site exposure, J. Virol., 78, 4541, 2004.

34. Cicala, C., Arthos, J., Rubbert, A., Selig, S., Wildt, K., Cohen, O.J., and Fauci, A.S., 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, 2000.

35. Penn, M.L., Grivel, J.C., Schramm, B., Goldsmith, M.A., and Margolis, L., CXCR4 utilization is sufficient to trigger CD4+ T cell depletion in HIV-1-infected human lymphoid tissue, Proc. Natl. Acad. Sci. U.S.A., 96, 663, 1999.

36. Katsikis, P.D., Wunderlich, E.S., Smith, C.A., and Herzenberg, L.A., Fas antigen stimulation induces marked apoptosis of T lymphocytes in human immunodeficiency virus-infected individuals, J. Exp. Med., 181, 2029, 1995.

37. de Oliveira Pinto, L.M., Garcia, S., Lecoeur, H., Rapp, C., and Gougeon, M.L., Increased sensitivity of T lymphocytes to tumor necrosis factor receptor 1 (TNFR1)- and TNFR2-mediated apoptosis in HIV infection: relation to expression of Bcl-2 and active caspase-8 and caspase-3, Blood, 99, 1666, 2002.

38. Zangerle, R., Gallati, H., Sarcletti, M., Wachter, H., and Fuchs, D., Tumor necrosis factor and soluble tumor necrosis factor receptors in individuals with human immunodeficiency virus infection, Immunol. Lett., 41, 229, 1994.

39. Zheng, L., Fisher, G., Miller, R.E., Peschon, J., Lynch, D.H., and Lenardo, M.J., Induction of apoptosis in mature T cells by tumour necrosis factor, Nature, 377, 348, 1995.

40. Alexander-Miller, M.A., Derby, M.A., Sarin, A., Henkart, P.A., and Berzofsky, J.A., Supraoptimal peptide-major histocompatibility complex causes a decrease in Bc1-2 levels and allows tumor necrosis factor receptor II-mediated apoptosis of cytotoxic T lymphocytes, J. Exp. Med., 188, 1391, 1998.

41. Lin, R.H., Hwang, Y.W., Yang, B.C., and Lin, C.S., TNF receptor-2-triggered apoptosis is associated with the downregulation of Bcl-xL on activated T cells and can be prevented by CD28 costimulation,

J. Immunol., 158, 598, 1997.

42. Bartz, S.R. and Emerman, M., Human immunodeficiency virus type 1 Tat induces apoptosis and increases sensitivity to apoptotic signals by up-regulating FLICE/caspase-8, J. Virol., 73, 1956, 1999.

43. Rasola, A., Gramaglia, D., Boccaccio, C., and Comoglio, P.M., Apoptosis enhancement by the HIV- 1 Nef protein, J. Immunol., 166, 81, 2001.

44. Stewart, S.A., Poon, B., Song, J.Y., and Chen, I.S., Human immunodeficiency virus type 1 Vpr induces apoptosis through caspase activation, J. Virol., 74, 3105, 2000.

45. Wang, Z.Q., Horowitz, H.W., Orlikowsky, T., Dudhane, A., Weinstein, A., and Hoffmann, M.K., Lymphocyte-reactive autoantibodies in human immunodeficiency virus type 1-infected persons facil­itate the deletion of CD8 T cells by macrophages, J. Infect. Dis., 178, 404, 1998.

46. Servet, C., Zitvogel, L., and Hosmalin, A., Dendritic cells in innate immune responses against HIV, Curr. Mol. Med., 2, 739, 2002.

47. Suzuki, S., Tobiume, M., Kameoka, M., Sato, K., Takahashi, T.A., Mukai, T., and Ikuta, K., Exposure of normal monocyte-derived dendritic cells to human immunodeficiency virus type-1 particles leads to the induction of apoptosis in co-cultured CD4+ as well as CD8⁺ T cells, Microbiol. Immunol., 44, 111, 2000.

48. Patterson, S., Rae, A., Hockey, N., Gilmour, J., and Gotch, F., Plasmacytoid dendritic cells are highly susceptible to human immunodeficiency virus type 1 infection and release infectious virus, J. Virol., 75, 6710, 2001.

49. Douek, D.C., Brenchley, J.M., Betts, M.R., Ambrozak, D.R., Hill, B.J., Okamoto, Y., Casazza, J.P., Kuruppu, J., Kunstman, K., Wolinsky, S., Grossman, Z., Dybul, M., Oxenius, A., Price, D.A., Connors M., and Koup, R.A., HIV preferentially infects HIV-specific CD4+ T cells, Nature, 417, 95, 2002.

50. Kuwana, M., Kaburaki J., Wright, T.M., Kawakami, Y., and Ikeda, Y., Induction of antigen-specific human CD4(+) T cell anergy by peripheral blood DC precursors, Eur. J. Immunol., 31, 2547, 2001.

51. McNeil, A.C., Shupert, W.L., Iyasere, C.A., Hallahan, C.W., Mican, J.A., Davey, R.T. Jr, and Connors, M., High-level HIV-1 viremia suppresses viral antigen-specific CD4(+) T cell proliferation, Proc. Natl. Acad. Sci. U.S.A., 98, 13878, 2001.

52. Belkaid, Y., Piccirillo, C.A., Mendez, S., Shevach, E.M., and Sacks, D.L., CD4+CD25+ regulatory T cells control Leishmania major persistence and immunity, Nature, 420, 502, 2002.

53. Gougeon, M.L., Lecoeur, H., Dulioust, A., Enouf, M.G., Crouvoiser, M., Goujard, C., Debord, T., and Montagnier, L., 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, 1996.

54. Miedema, F., Petit, A.J., Terpstra, F.G., Schattenkerk, J.K., De Wolf, F., Al, B.J., Ross, M., Lange, J.M., Danner, S.A., Goudsmith, J., Immunological abnormalities in human immunodeficiency virus (HIV)-infected asymptomatic homosexual men. HIV affects the immune system before CD4+ T helper cell depletion occurs, J. Clin. Invest., 82, 1908, 1988.

55. Clerici, M., Lucey, D.R., Berzofsky, J.A., Pinto, L.A., Wynn, T.A., Blatt, S.P., Dolan, M.J., Hendrix,

C. W., Wolf, S.F., and Shearer, G.M., Restoration of HIV-specific cell-mediated immune responses by interleukin-12 in vitro, Science, 262, 1721, 1993.

56. Graziosi, C., Pantaleo, G., Gantt, K.R., Fortin, J.P., Demarest, J.F., Cohen, O.J., Sekaly, R.P., and Fauci, A.S., Lack of evidence for the dichotomy of TH1 and TH2 predominance in HIV-infected individuals, Science, 265, 248, 1994.

57. Meyaard, L., Otto, S.A., Jonker, R.R., Mijnster, M.J., Keet, R.P.M., and Miedema, F., Programmed death of T cells in HIV-1 infection, Science, 257, 217, 1992.

58. Gougeon, M.L., Lecoeur, H., Boudet, F., Ledru, E., Marzabal, S., Boullier, S., Roue, R., Nagata, S., and Heeney, J., Lack of chronic immune activation in HIV-infected chimpanzees correlates with the resistance of T cells to Fas/Apo-1 (CD95)-induced apoptosis and preservation of a T helper 1 phenotype, J. Immunol., 158, 2964, 1997.

59. Gehri, R., Hahn, S., Rothen, M. Steuerwald, M., Nuesch, R., and Erb, P., The Fas receptor in HIV infection: expression on peripheral blood lymphocytes and role in the depletion of T cells, AIDS, 10, 9, 1996.

60. Kobayashi, N., Hamamoto, Y., Yamamoto, N., Ishii, A., Yonehara, M., and Yonehara, S., Anti-Fas monoclonal antibody is cytocidal to human immunodeficiency virus-infected cells without augmenting viral replication, Proc. Natl. Acad. Sci. U.S.A., 87, 9620, 1990.

61. Silvestris, F., Cafforio, P., Frassanito, M.A., Tucci, M., Romito, A., Nagata, S., and Dammacco, F., Overexpression of Fas antigen on T cells in advanced HIV-1 infection: differential ligation constantly induces apoptosis, AIDS, 10, 131, 1996.

62. Aries, S.P., Schaaf, B., Muller, C., Dennin, R.H., and Dalhoff, K., Fas (CD95) expression on CD4+ T cells from HIV-infected patients increases with disease progression, J. Mol. Med., 73, 591, 1995.

63. Westendorp, M.O., Frank, R., Ochsenbauer, C., Stricker, K., Dhein, J., Walczak, H., Debatin, K.M., and Krammer, P.H., Sensitization of T cells to CD95-mediated apoptosis by HIV-1 Tat and gp120, Nature, 375, 497, 1995.

64. Baumler, C.B., Bohler, T., Herr, I., Benner, A., Krammer, P.H., and Debatin, K.M., Activation of the CD95 (APO-1/Fas) system in T cells from human immunodeficiency virus type-1-infected children, Blood, 88, 1741, 1996.

65. Piazza, C., Gilardini Montani, M.S., Moretti, S., Cundari, E., and Piccolella, E., Cutting edge: CD4+ T cells kill CD8+ T cells via Fas/Fas ligand-mediated apoptosis, J. Immunol., 158, 1503, 1997.

66. Garcia, S., Fevrier, M., Dadaglio, G., Lecoeur, H., Riviere, Y., and Gougeon, M.L., Potential deleterious effect of anti-viral cytotoxic lymphocyte through the CD95 (FAS/APO-1)-mediated pathway during chronic HIV infection, Immunol. Lett., 57, 53, 1997.

67. Szondy, Z., Lecoeur, H., Fesus, L., and Gougeon, M.L., All-trans retinoic acid inhibition of anti-CD3- induced T cell apoptosis in human immunodeficiency virus infection mostly concerns CD4 T lym­phocytes and is mediated via regulation of CD95 ligand expression, J. Infect. Dis., 178, 1288, 1998.

68. Yang, Y., Mercep, M., Ware, C.F., and Ashwell, J.D., Fas and activation-induced Fas ligand mediate apoptosis of T cell hybridomas: inhibition of Fas ligand expression by retinoic acid and glucocorti­coids, J. Exp. Med., 181, 1673, 1995.

69. Mueller, Y.M., de Rosa, S.C., Hutton, J.A., Witek, J., Roederer, M., Altman, J.D., and Katskikis, P.D., Increased CD95/Fas-induced apoptosis of HIV-specific CD8(+) T cells, Immunity, 15, 871, 2001.

70. Bofill, M., Gombert, W., Borthwick, N.J., Akbar, A.N., McLaughlin, J.E., Lee, C.A., Johnson, M.A., Pinching, A.J., and Janossy, G., 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, 1995.

71. Boudet, F., Lecoeur, H., and Gougeon, M.L., Apoptosis associated with ex vivo down-regulation of Bcl-2 and upregulation of Fas in potential cytotoxic CD8+ T lymphocytes during HIV infection, J. Immunol., 156, 2282, 1996.

72. Adachi, Y., Oyaizu, N., Than, S., McCloskey, T.W., and Pahwa, S., IL-2 rescues in vitro lymphocyte apoptosis in patients with HIV infection: correlation with its ability to block culture-induced down­modulation of Bcl-2, J. Immunol., 157, 4184, 1996.

73. Naora, H. and Gougeon, M.L., 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, 1999.

74. Bulfone-Paus, S., Ungureanu, D., Pohl, T., Lindner, G., Paus, R., Ruckert, R., Krause, H., and Kunzendorf, U., Interleukin-15 protects from lethal apoptosis in vivo, Nat. Med., 3, 1124, 1997.

75. Estaquier, J., Tanaka, M., Suda, T., Nagata, S., Golstein, P., and Ameisen, J.C., 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, 1996.

76. Chen, H., Yip, Y.K., George, I., Tyorkin, M., Salik, E., and Sperber, K., Chronically HIV-1-infected monocytic cells induce apoptosis in cocultured T cells, J. Immunol., 161, 4257, 1998.

77. Flamand, L., Crowley, R.W., Luso, P., Colombini-Hatch, S., Margolis, D.M., and Gallo, R.C., Acti­vation of CD8+ T lymphocytes through the T cell receptor turns on CD4 gene expression: implications for HIV pathogenesis, Proc. Natl. Acad. Sci. U.S.A., 95, 3111, 1998.

78. Yang, L.P., Riley, J.L., Carroll, R.G., June, C.H., Hoxie, J., Patterson, B.K., Ohshima, Y., Hodes, R.J., and Delespesse, G., Productive infection of neonatal CD8+ T lymphocytes by HIV-1, J. Exp. Med., 187, 1139, 1998.

79. Pinto, L.A., Williams, M.S., Dolan, M.J., Henkart, P.A., and Shearer, G.M., β-Chemokines inhibit activation-induced death of lymphocytes from HIV-infected individuals, Eur. J. Immunol., 30, 2048, 2000.

80. Blanco, J., Barretin, J., Henson, G., Bridger, G., De Clercq, E., Clotet, B., and Este, J.A., The CXCR4 antagonist AMD3100 efficiently inhibits cell-surface-expressed human immunodeficiency virus type 1 envelope-induced apoptosis, Antimicrob. Agents Chemother., 44, 51, 2000.

81. Decrion, A.Z., Varin, A., Estavoyer, J.M., and Herbein, G., CXCR4-mediated T cell apoptosis in HIV infection, J. Gen. Virol., 85, 1471, 2004.

82. Blanco, J., Jacotot, E., Cabrera, C., Cardona, A., Clotet, B., De Clercq, E., and Este, J.A., The implication of the chemokine receptor CXCR4 in HIV-1 envelope protein-induced apoptosis is inde­pendent of the G protein-mediated signalling, AIDS, 13, 909, 1999.

83. Lee, C., Liu, Q.H., Tomkowicz, B., Yi, Y., Freedman, B.D., and Collman, R.G., Macrophage activation through CCR5- and CXCR4-mediated gp120-elicited signaling pathways, J. Leukoc. Biol., 74, 676, 2003.

84. Jewett, A., Cavalcanti, M., Giorgi, J., and Bonavida, B., Concomitant killing in vitro of both gp120- coated CD4+ peripheral T lymphocytes and natural killer cells in the antibody-dependent cellular cytotoxicity (ADCC) system, J. Immunol., 158, 5492, 1997.

85. Kaul, M. and Lipton, S.A., Chemokines and activated macrophages in HIV gp120-induced neuronal apoptosis, Proc. Natl. Acad. Sci. U.S.A., 96, 8212, 1999.

86. Zauli, G., Gibellini, D., Secchiero, P., Dutartre, H., olive, D., Capitani, S., and Collette, Y., 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, 1999.

87. Li, C.J., Friendman, D.J., Wang, C., Metelev, V., and Parde, A.B., Induction of apoptosis in uninfected lymphocytes by HIV-1 Tat protein, Science, 268, 429, 1995.

88. James, C.O., Huang, M.B., Khan, M., Garcia-Barrio, M., Powell, M.D., and Bond, V.C., Extracellular Nef protein targets CD4+ T cells for apoptosis by interacting with CXCR4 surface receptors, J. Virol., 78, 3099, 2004.

89. Jacotot, E., Ravagnan, L., Loeffler, M., Ferri, K.F., Vieira, H.L., Zamzami, N., Costantini, P., Druil- lennec, S., Hoebeke, J., Briand, J.P., Irinopoulo, T., Daugas, E., Susin, S.A., Cointe, D., Xie, Z.H., Reed, J.C., Rocques, B.P., and Kroemer, G., The HIV-1 viral protein R induces apoptosis via a direct effect on the mitochondrial permeability transition pore, J. Exp. Med., 191, 33, 2000.

90. Jacotot, E.Ferri, K.F., El Hamel, C., Brenner, C., Druillennec, S., Hoebeke, J., Rustin, P., Metivier,

D., Lenoir, C., Geuskens, M., Vieira, H.L., Loeffler, M., Belzacqu, A.S., Briand, J.P., Zamzami, N., Edelman, L., Xie, Z.H., Reed, J.C., Roques, B.P., and Kroemer, G., Control of mitochondrial mem­brane permeabilization by adenine nucleotide translocator interacting with HIV-1 viral protein R and Bcl-2, J. Exp. Med., 193, 509, 2001.

91. Roumier T., Vieira, H.L., Castedo, M, Ferri, K.F., Boya, P., Andreau, K., Druillennec, S., Joza, N., Penninger, J.M., Roques, B., and Kroemer, G., The C-terminal moiety of HIV-1 Vpr induces cell death via caspase-independent mitochondrial pathway, Cell Death Diff., 9, 1212, 2002.

92. Yi, Y., Chen, W., Frank, I., Cutilli, J., Singh, A., Starr-Spires, L., Sulcove, J., Kolson, D.L., and Collman, R.G., An unusual syncytia-inducing human immunodeficiency virus type 1 primary isolate from the central nervous system that is restricted to CXCR4, replicates efficiently in macrophages, and induces neuronal apoptosis, J. Neurovirol., 9, 432, 2003.

93. Sperber, K., Beuria, P., Singha, N., Gelman, I., Cortes, P., Chen, H., and Kraus, T., Induction of apoptosis by HIV-1-infected monocytic cells, J. Immunol., 170, 1566, 2003.

94. Miura, Y., Misawa, N., Kawano, Y., Okada, H., Inagaki, Y., Yamamoto, N., Ito, M., Yagita, H., Okumura,

K., and Mizusawa, H., Tumor necrosis factor-related apoptosis-inducing ligand induces neuronal death in a murine model of HIV central nervous system infection, Proc. Natl. Acad. Sci. U.S.A., 100, 2777, 2003.

95. Tong, N., Perry, S.W., Zhang, Q., James, H.J., Guo H., Brooks, A., Bal, H., Kinnear, S.A., Fine, S., Epstein, L.G., Dairaghi, D., Schall, T.J., Gendelman, H.E., Dewhurst, S., Sharer, L.R., and Gelbard, H.A., Neuronal fractalkine expression in HIV-1 encephalitis: roles for macrophage recruitment and neuroprotection in the central nervous system, J. Immunol., 164, 1333, 2000.

96. Muro-Cacho, C.A., Pantaleo, G., and Fauci, A.S., Analysis of apoptosis in lymph nodes of HIV- infected persons. Intensity of apoptosis correlates with the general state of activation of the lymphoid tissue and not with stage of disease or viral burden, J. Immunol., 154, 5555, 1995.

97. Amendola, A., Gougeon, M.L., Poccia, F., Bondurand, A., Fesus, L., and Piacentini, M., 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. U.S.A., 93, 11057, 1996.

98. Chen, J.J., Huang, J.C., Shirtliff, M., Briscoe, E., Ali, S., Cesani, F., Paar, D., and Cloyd, M.W., CD4 lymphocytes in the blood of HIV(+) individuals migrate rapidly to lymph nodes and bone marrow: support for homing theory of CD4 cell depletion, J. Leukoc. Biol., 72, 271, 2002.

99. Wang, L., Chen, J.J., Gelman, B.B., Konig, R., and Cloyd, M.W., A novel mechanism of CD4 lymphocyte depletion involves effects of HIV on resting lymphocytes: induction of lymph node homing and apoptosis upon secondary signaling through homing receptors, J. Immunol., 162, 268,

1999.

100. Hildeman, D.A., Zhu, Y., Mitchell, T.C., Bouillet, P., Strasser, A., Kappler, J., and Marrack, P., Activated T cell death in vivo mediated by proapoptotic Bcl-2 family member Bim, Immunity, 16, 759, 2002.

101. Etemad-Moghadam, B., Sun, Y., Nicholson, E.K., Fernandes, M., Liou, K., Gomila, R., Lee, J., and Sodroski, J., Envelope glycoprotein determinants of increased fusogenicity in a pathogenic simian­human immunodeficiency virus (SHIV-KB9) passaged in vivo, J. Virol., 74, 4433, 2000.

102. Blaak, H., Van't Wout, A.B., Brouwer, M., Hooibrink, B., Hovenkamp, E., and Schuitemaker, H., In vivo HIV-1 infection of CD45RA(+)CD4(+) T cells is established primarily by syncytium-inducing variants and correlates with the rate of CD4(+) T cell decline, Proc. Natl. Acad. Sci. U.S.A., 97, 1269,

2000.

103. Badley, A.D., Parato, K., Cameron, D.W., Kravcik, S., Phenix, B.N., Ashby, D., Kumar, A., Lynch, D.H., Tschopp, J., and Angel, J.B., Dynamic correlation of apoptosis and immune activation during treatment of HIV infection, Cell Death Differ., 6, 420, 1999.

104. Chavan, S.J., Tamma, S.L., Kaplan, M., Gersten, M., and Pahwa, S.G., Reduction in T cell apoptosis in patients with HIV disease following antiretroviral therapy, Clin. Immunol., 93, 24, 1999.

105. Kotler, D.P., Shimada, T., Snow, G., Winson, G., Chen, W., Zhao, M., Inada, Y., and Clayton, F., Effect of combination antiretroviral therapy upon rectal mucosal HIV RNA burden and mononuclear cell apoptosis, AIDS, 12, 597, 1998.

106. Johnson, N. and Parkin, J.M., Anti-retroviral therapy reverses HIV-associated abnormalities in lym­phocyte apoptosis, Clin. Exp. Immunol., 113, 229, 1998.

107. Aries, S.P., Weyrich, K., Schaaf, B., Hansen, F., Dennin, R.H., and Dalhoff, K., Early T-cell apoptosis and Fas expression during antiretroviral therapy in individuals infected with human immunodeficiency virus-1, Scand. J. Immunol., 48, 86, 1998.

108. Badley, A.D., Dockrell, D.H., Algeciras, A., Ziesmer, S., Landay, A., Lederman, M.M., Connick, E., Kessler, H., Kuritzkes, D., Lynch, D.H., Roche, P., Yagita, H., and Paya, C.V., In vivo analysis of Fas/FasL interactions in HIV-infected patients, J. Clin. Invest., 102, 79, 1998.

109. Bohler, T., Walcher, J., Holzl-Wenig, G., Geiss, M., Buchholz, B., Linde, R., and Debatin, K.M., Early effects of antiretroviral combination therapy on activation, apoptosis and regeneration of T cells in HIV-1-infected children and adolescents, AIDS, 13, 779, 1999.

110. Sloand, E.M., Kumar, P.N., Kim, S., Chaudhuri, A., Weichold, F.F., and Young, N.S., Human immu­nodeficiency virus type 1 protease inhibitor modulates activation of peripheral blood CD4(+) T cells and decreases their susceptibility to apoptosis in vitro and in vivo, Blood, 94, 1021, 1999.

111. Phenix, B.N., Angel, J.B., Mandy, F., Kravcik, S., Parato, K., Chambers, K.A., Gallicano, K., Hawley- Foss, N., Casol, S., Camerson, D.W., and Badley, A.D., Decreased HIV-associated T cell apoptosis by HIV protease inhibitors, AIDS Res. Hum. Retroviruses, 16, 559, 2000.

112. Arnoult, D., Petit, F., Lelievre, J.D., Lecossier, D., Hance, A., Monceaux, V., Hurtrel, B., Ho Tsong Fang R, and Ameisen, J.C., Caspase-dependent and -independent T-cell death pathways in pathogenic simian immunodeficiency virus infection: relationship to disease progression, Cell Death Differ., 10, 1240, 2003.

113. Monceaux, V., Estaquier, J., Fevrier, M., Cumont, M.C., Riviere, Y., Aubertin, A.M., Ameisen, J.C., and Hurtrel, B., Extensive apoptosis in lymphoid organs during primary SIV infection predicts rapid progression towards AIDS, AIDS, 17, 1585, 2003.

114. Tesselaar, K., Arens, R., van Schijndel, G.M., Baars, P.A., van der Valk, M.A., Borst, J., van Oers, M.H., and van Lier, R.A., Lethal T cell immunodeficiency induced by chronic costimulation via CD27­CD70 interactions, Nat. Immunol., 4, 49, 2003.

115. Wang, X.Z., Stepp, S.E., Brehm, M.A., Chen, H.D., Selin, L.K., and Welsh, R.M., Virus-specific CD8 T cells in peripheral tissues are more resistant to apoptosis than those in lymphoid organs, Immunity, 18, 631, 2003.

116. Schrager, L.K. and D’Souza, M.P., Cellular and anatomical reservoirs of HIV-1 in patients receiving potent antiretroviral combination therapy, JAMA, 280, 67, 1998.

117. Finzi, D., Blankson, J., Siliciano, J.D., Margolick, J.B., Chadwick, K., Pierson, T., Smith, K., Lisz- iewicz, J., Lori, F., Flexner, C., Quinn, T.C., Chaisson, R.E., Rosenberg, E., Walker, B., Gange, S., Gallant, J., and Siliciano, R.F., Latent infection of CD4+ T cells provides a mechanism for lifelong persistence of HIV-1, even in patients on effective combination therapy, Nat. Med., 5, 512, 1999.

118. Ho, D.D., Toward HIV eradication or remission: the tasks ahead, Science, 280, 1866, 1998.

119. Wein, L.M., D’Amato, R.M., and Perelson, A.S., Mathematical analysis of antiretroviral therapy aimed at HIV-1 eradication or maintenance of low viral loads, J. Theor. Biol., 192, 81, 1998.

120. Mahlknecht, U. and Herbein, G., Macrophages and T-cell apoptosis in HIV infection: a leading role for accessory cells? Trends Immunol., 22, 256, 2001.

121. Swingler, S., Mann, A., Jacque, J., Brichacek, B., Sasseville, V.G., Williams, K., Lackner, A.A., Janoff

E. N., Wang, R., Fisher, D., and Stevenson, M., HIV-1 Nef mediates lymphocyte chemotaxis and activation by infected macrophages, Nat. Med., 5, 997, 1999.

122. Swingler, S., Brichacek, B., Jacque, J.M., Ulich, C., Zhou, J., and Stevenson, M., HIV-1 Nef intersects the macrophage CD40L signalling pathway to promote resting-cell infection, Nature, 424, 213, 2003.

123. Mahlknecht, U., Deng, C., Lu, M.C., Greenough, T.C., Sullivan, J.L., O’Brien, W.A., and Herbein, G., Resistance to apoptosis in HIV-infected CD4+ T lymphocytes is mediated by macrophages: role for Nef and immune activation in viral persistence, J. Immunol., 165, 6437, 2000.

124. Geleziunas, R., Xu, W., Takeda, K., Ichijo, H., and Greene, W.C., HIV-1 Nef inhibits ASK1-dependent death signalling providing a potential mechanism for protecting the infected host cell, Nature, 410, 834, 2001.

125. Ott, M., Emiliani, S., Van Lint, C., Herbein, G., Lovett, J., Chirmule, N., McCloskey, T., Pahwa, S., and Verdin E., Immune hyperactivation of HIV-1-infected T cells mediated by Tat and the CD28 pathway, Science, 275, 1481, 1997.

126. Westendorp, M.O., Li-Weber, M., Frank, R.W., and Krammer, P.H., Human immunodeficiency virus type 1 Tat upregulates interleukin-2 secretion in activated T cells, J. Virol., 68, 4177, 1994.

127. Zhang, Z., Schuler, T., Zupantic, M., Wietgrefe, S., Staskus, K.A., Reimann, K.A., Reinhart, T.A., Rogan, M., Cavert, W., Miller, C.J., Veazey, R.S., Notermans, D., Little, S., Danner, S.A., Richman, D.d., Havlir, D., Wong, J., Jordan, H.L., Schacker, T.W., Racz, P., Tenner-Racz, K., Letvin N.L., Wolinsky, S., and Haase, A.T., Sexual transmission and propagation of SIV and HIV in resting and activated CD4+ T cells, Science, 286, 1353, 1999.

128. Vocero-Akbani, A.M., Heyden, N.V., Lissy, N.A., Ratner, L., and Dowdy, S.F., Killing HIV-infected cells by transduction with an HIV protease-activated caspase-3 protein, Nat. Med., 5, 29, 1999.