CONCLUDING REMARKS
Progression of HIV is intimately related to the loss of lymphocytes. Because these cells play vital roles in maintaining and augmenting immune responses, any decline in their numbers results in deficits in both humoral and cell-mediated immunity.
AICD of lymphocytes has specific consequences relating to the pathogenesis of HIV disease, including loss of memory responses, impaired CTL function, and cytokine dysregulation. The immune activation that characterizes the chronic state of HIV infection occurs as the result of various virus-specific and nonspecific causes. Attrition of the memory T cell pools by repeated immune activation events and depletion of naive T cells may account for the increased susceptibility to opportunistic infections and malignancies observed with HIV infection. Preferential targeting of CD4 T cells for AICD may explain, in part, some of the CTL dysfunction observed in HIV. The cytokine dysregulation that occurs in HIV disease has the potential to play a pivotal role in pathogenesis, as type-1 and type-2 cytokines have the potential to either inhibit or enhance AICD, respectively. Additional evidence that immune activation is linked to apoptosis in HIV infection stems from recent studies that suggest that increases in immune activation observed in other pathogenic states also correlate with increases in cell death, as, for example, is seen in certain septic states.110 An understanding of the means to control immune activation has the potential of converting a lethal progressive disease into one in which the host and the pathogen can live in harmony, as in the sooty mangabeys and some cases of LTNPs.REFERENCES
1. Butz, E.A. and Bevan, M.J., Massive expansion of antigen-specific CD8+ T cells during an acute virus infection, Immunity, 8(2), 167-175, 1998.
2. Pantaleo, G., Demarest, J.F., Soudeyns, H., Graziosi, C., Denis, F., Adelsberger, J.W., Borrow, P., Saag, M.S., Shaw, G.M., Sekaly, R.P., Major expansion of CD8+ T cells with a predominant V usage during the primary immune response to HIV, Nature, 370(6489), 463-467, 1994.
3. Doisne, J.M., Urrutia, A., Lacabaratz-Porret, C., Goujard, C., Meyer, L., Chaix, M.L., Sinet, M., Venet, A., CD8+ T cells specific for EBV, cytomegalovirus, and influenza virus are activated during primary HIV infection, J. Immunol., 173(4), 2410-2418, 2004.
4. Papagno, L., Spina, C.A., Marchant, A., Salio, M., Rufer, N., Little, S., Dong, T., Chesney, G., Waters, A., Easterbrook, P., Dunbar, P.R., Shepherd, D., Cerundolo, V., Emery, V., Griffiths, P., Conlon, C., McMichael, A.J., Richman, D.D., Rowland-Jones, S.L., Appay, V., Immune activation and CD8(+) T- cell differentiation towards senescence in HIV-1 infection. PLoS Biol., 2(2), E20, 2004.
5. Giorgi, J.V., Fahey, J.L., Smith, D.C., Hultin, L.E., Cheng, H.L., Mitsuyasu, R.T., Detels, R., Early effects of HIV on CD4 lymphocytes in vivo, J. Immunol., 138(11), 3725-3730, 1987.
6. Chun, T.W., Justement, J.S., Sanford, C., Hallahan, C.W., Planta, M.A., Loutfy, M., Kottilil, S., Moir, S., Kovacs, C., Fauci, A.S., Relationship between the frequency of HIV-specific CD8+ T cells and the level of CD38+CD8+ T cells in untreated HIV-infected individuals, Proc. Natl. Acad. Sci. U.S.A., 101(8), 2464-2469, 2004.
7. Sousa, A.E., Carneiro, J., Meier-Schellersheim, M., Grossman, Z., Victorino, R.M., CD4 T cell depletion is linked directly to immune activation in the pathogenesis of HIV-1 and HIV-2 but only indirectly to the viral load, J. Immunol., 169(6), 3400-3406, 2002.
8. Mildvan, D., Bosch, R.J., Kim, R.S., Spritzler, J., Haas, D.W., Kuritzkes, D., Kagan, J., Nokta, M., DeGruttola, V., Moreno, M., Landay, A., Immunophenotypic markers and antiretroviral therapy (IMART): T cell activation and maturation help predict treatment response, J. Infect. Dis., 189(10), 1811-1820, 2004.
9. Tolstrup, M., Ostergaard, L., Laursen, A.L., Pedersen, S.F., Duch, M., HIV/SIV escape from immune surveillance: focus on Nef, Curr. HIV Res., 2(2), 141-151, 2004.
10. Oyaizu, N., McCloskey, T.W., Coronesi, M., Chirmule, N., Kalyanaraman, V.S., 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(11), 3392-3400, 1993.
11. McCloskey, T.W., Ott, M., Tribble, E., Khan, S.A., Teichberg, S., Paul, M.O., Pahwa, S., Verdin, E., Chirmule, N., Dual role of HIV Tat in regulation of apoptosis in T cells, J. Immunol., 158(2), 1014-1019, 1997.
12. Gaynor, E. and Chen, I.S., Analysis of apoptosis induced by HIV-1 Vpr and examination of the possible role of the hHR23A protein, Exp. Cell Res., 267(2), 243-257, 2001.
13. Simmons, A., Aluvihare, V., and McMichael, A., Nef triggers a transcriptional program in T cells imitating single-signal T cell activation and inducing HIV virulence mediators, Immunity, 14(6), 763-777, 2001.
14. Kinter, A.L., Craig, A., Umscheid, J.A., Claudia C., Yin L., Robert J., Eileen D., Linda E., Joseph A., Ronald L.R., and Anthony S.F., HIV envelope induces virus expression from resting CD4+ T cells isolated from HIV-infected individuals in the absence of markers of cellular activation or apoptosis,
J. Immunol., 170(5), 2449-2455, 2003.
15. Stoddart, C.A., Geleziunas, R., Ferrell, S., Linquist-Stepps, V., Moreno, M.E., Bare, C., Xu, W., Yonemoto, W., Bresnahan, P.A., McCune, J.M., Greene, W.C., Human immunodeficiency virus type 1 Nef-mediated downregulation of CD4 correlates with Nef enhancement of viral pathogenesis, J. Virol., 77(3), 2124-2133, 2003.
16. Lahti, A.L., Manninen, A., and Saksela, K., Regulation of T cell activation by HIV-1 accessory proteins: Vpr acts via distinct mechanisms to cooperate with Nef in NFAT-directed gene expression and to promote transactivation by CREB, Virology, 310(1), 190-196, 2003.
17. Bentwich, Z., Kalinkovich, A., and Weisman, Z., Immune activation is a dominant factor in the pathogenesis of African AIDS, Immunol. Today, 16(4), 187-191, 1995.
18. Bafica, A., Scanga, C.A., Schito, M., Chaussabel, D., Sher, A., Influence of coinfecting pathogens on HIV expression: evidence for a role of Toll-like receptors, J. Immunol., 172(12), 7229-7234, 2004.
19. Silvestri, G., Sodora, D.L., Koup, R.A., Paiardini, M., O'Neil, S.P., McClure, H.M., Staprans, S.I., Feinberg, M.B., Nonpathogenic SIV infection of sooty mangabeys is characterized by limited bystander immunopathology despite chronic high-level viremia, Immunity, 18(3), 441-452, 2003.
20. Giorgi, J.V., Lyles, R.H., Matud, J.L., Yamashita, T.E., Mellors, J.W., Hultin, L.E., Jamieson, B.D., Margolick, J.B., Rinaldo, C.R. Jr, Phair, J.P., Detels, R., Multicenter AIDS Cohort Study., Predictive value of immunologic and virologic markers after long or short duration of HIV-1 infection, J. Acquir. Immune Defic. Syndr., 29(4), 346-355, 2002.
21. Pahwa, S., Pahwa, R., Saxinger, C., Gallo, R.C., Good, R.A., Influence of the human T-lymphotropic virus/lymphadenopathy-associated virus on functions of human lymphocytes: evidence for immunosuppressive effects and polyclonal B-cell activation by banded viral preparations, Proc. Natl. Acad. Sci. U.S.A., 82(23), 8198-8202, 1985.
22. Lane, H.C., Masur, H., Edgar, L.C., Whalen, G., Rook, A.H., Fauci, A.S., Abnormalities of B-cell activation and immunoregulation in patients with the acquired immunodeficiency syndrome, N. Engl.
J. Med., 309(8), 453-458, 1983.
23. Johansson, C.C., Bryn, T., Yndestad, A., Eiken, H.G., Bjerkeli, V., Froland, S.S., Aukrust, P., Tasken,
K., Cytokine networks are pre-activated in T cells from HIV-infected patients on HAART and are under the control of cAMP, AIDS, 18(2), 171-179, 2004.
24. Poli, G., T lymphocytes of HIV-positive individuals: preloaded guns in spite of highly active antiretroviral therapy? AIDS, 18(2), 327-328, 2004.
25. Moir, S., Malaspina, A., Ogwaro, K.M., Donoghue, E.T., Hallahan, C.W., Ehler, L.A., Liu, S., Adelsberger, J., Lapointe, R., Hwu, P., Baseler, M., Orenstein, J.M., Chun, T.W., Mican, J.A., Fauci, A.S., HIV-1 induces phenotypic and functional perturbations of B cells in chronically infected individuals, Proc. Natl. Acad. Sci. U.S.A., 98(18), 10362-10367, 2001.
26. Gougeon, M.-L., Lecoeur, H., Dulioust, A., Enouf, M.G., Crouvoiser, M., Goujard, C., Debord, T., 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,(9): 3509-3521, 1996.27. Miedema, F., Petit, A.J., Terpstra, F.G., Schattenkerk, J.K., de Wolf, F., Al, B.J., Roos, M., Lange, J.M., Danner, S.A., Goudsmit, 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(6), 1908-1914, 1988.
28. Deeks, S.G. and Walker, B.D., The immune response to AIDS virus infection: good, bad, or both? J. Clin. Invest., 113(6), 808-810, 2004.
29. Paiardini, M., Cervasi, B., Dunham, R., Sumpter, B., Radziewicz, H., Silvestri, G., Cell-cycle dys- regulation in the immunopathogenesis of AIDS, Immunol. Res., 29(1-3), 253-268, 2004.
30. Takeda, K., Kaisho, T., and Akira, S., Toll-like receptors, Annu. Rev. Immunol., 21, 335-376, 2003.
31. Wraith, D.C., Nicolson, K.S., and Whitley, N.T., Regulatory CD4+ T cells and the control of autoimmune disease, Curr. Opin. Immunol., 16(6), 695-701, 2004.
32. Fehervari, Z. and Sakaguchi, S., Control of Foxp3+ CD25+CD4+ regulatory cell activation and function by dendritic cells, Int. Immunol., 16(12), 1769-1780, 2004.
33. Chen, T.C., Cobbold, S.P., Fairchild, PJ., Waldmann, H., Generation of anergic and regulatory T cells following prolonged exposure to a harmless antigen, J. Immunol., 172(10), 5900-5907, 2004.
34. Groux, H., Fournier, N., and Cottrez, F., Role of dendritic cells in the generation of regulatory T cells, Semin. Immunol., 16(2), 99-106, 2004.
35. Kinter, A.L., Hennessey, M., Bell, A., Kern, S., Lin, Y., Daucher, M., Planta, M., McGlaughlin, M., Jackson, R., Ziegler, S.F., Fauci, A.S., CD25+CD4+ regulatory T cells from the peripheral blood of asymptomatic HIV-infected individuals regulate CD4+ and CD8+ HIV-specific T cell immune responses in vitro and are associated with favorable clinical markers of disease status, J.
Exp. Med., 200(3), 331-343, 2004.36. Barry, A.P., Chavan, R., Wernett, M., McCausland, M., Staprans, S., Silvestri, G., and Feinberg, M.B., Differences in Dendritic Cell Populations and Signaling May Account for Divergent SIV Infection Outcomes in Rhesus Macaques and Sooty Mangabeys, paper presented at 11th Conference on Retroviruses and Opportunistic Infections, San Francisco, CA, 2004.
37. Kottilil, S., Chun, T.W., Moir, S., Liu, S., McLaughlin, M., Hallahan, C.W., Maldarelli, F., Corey, L., Fauci, A.S., Innate immunity in human immunodeficiency virus infection: effect of viremia on natural killer cell function, J. Infect. Dis., 187(7), 1038-1045, 2003.
38. Poles, M.A., Barsoum, S., Yu, W., Yu, J., Sun, P., Daly, J., He, T., Mehandru, S., Talal, A., Markowitz, M., Hurley, A., Ho, D., Zhang, L., Human immunodeficiency virus type 1 induces persistent changes in mucosal and blood T cells despite suppressive therapy, J. Virol., 77(19), 10456-10467, 2003.
39. Deeks, S.G., Kitchen, C.M., Liu, L., Guo, H., Gascon, R., Narvaez, A.B., Hunt, P., Martin, J.N., Kahn, J.O., Levy, J., McGrath, M.S., Hecht, F.M., Immune activation set point during early HIV infection predicts subsequent CD4+ T-cell changes independent of viral load, Blood, 104(4), 942-947, 2004.
40. Hunt, P.W., Martin, J.N., Sinclair, E., Bredt, B., Hagos, E., Lampiris, H., Deeks, S.G., T cell activation is associated with lower CD4+ T cell gains in human immunodeficiency virus-infected patients with sustained viral suppression during antiretroviral therapy, J. Infect. Dis., 187(10), 1534-1543, 2003.
41. McMichael, A.J. and Rowland-Jones, S.L., Cellular immune responses to HIV, Nature, 410(6831), 980-987, 2001.
42. Wherry, E.J., Teichgraber, V., Becker, T.C., Masopust, D., Kaech, S.M., Antia, R., von Andrian, U.H., Ahmed, R., Lineage relationship and protective immunity of memory CD8 T cell subsets, Nat. Immunol., 4(3), 225-234, 2003.
43. Appay, V., Dunbar, P.R., Callan, M., Klenerman, P., Gillespie, G.M., Papagno, L., Ogg, G.S., King, A., Lechner, F., Spina, C.A., Little, S., Havlir, D.V., Richman, D.D., Gruener, N., Pape, G., Waters, A., Easterbrook, P., Salio, M., Cerundolo, V., McMichael, A.J., Rowland-Jones, S.L., Memory CD8+ T cells vary in differentiation phenotype in different persistent virus infections, Nat. Med., 8(4), 379-385, 2002.
44. van Lier, R.A., ten Berge, I.J., and Gamadia, L.E., Human CD8(+) T-cell differentiation in response to viruses, Nat. Rev. Immunol., 3(12), 931-939, 2003.
45. Champagne, P., Ogg, G.S., King, A.S., Knabenhans, C., Ellefsen, K., Nobile, M., Appay, V., Rizzardi, G.P., Fleury, S., Lipp, M., Forster, R., Rowland-Jones, S., Sekaly, R.P., McMichael, A.J., Pantaleo, G., Skewed maturation of memory HIV-specific CD8 T lymphocytes, Nature, 410(6824), 106-111, 2001.
46. 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,. Koup, R.A., HIV preferentially infects HIV-specific CD4+ T cells, Nature, 417(6884), 95-98, 2002.
47. Speth, C., Joebstl, B., Barcova, M., Dierich, M.P., HIV-1 envelope protein gp41 modulates expression of interleukin-10 and chemokine receptors on monocytes, astrocytes and neurones, AIDS, 14(6), 629-636, 2000.
48. Sallusto, F., Lenig, D., Forster, R., Lipp, M., Lanzavecchia, A., Two subsets of memory T lymphocytes with distinct homing potentials and effector functions, Nature, 401(6754), 708-712, 1999.
49. Silvestri, G. and Feinberg, M.B., Turnover of lymphocytes and conceptual paradigms in HIV infection, J. Clin. Invest., 112(6), 821-824, 2003.
50. Effros, R.B., Telomeres and HIV disease, Microbes Infect., 2(1), 69-76, 2000.
51. Migueles, S.A., Laborico, A.C., Shupert, W.L., Sabbaghian, M.S., Rabin, R., Hallahan, C.W., Van Baarle, D., Kostense, S., Miedema, F., McLaughlin, M., Ehler, L., Metcalf, J., Liu, S., Connors, M., HIV-specific CD8+ T cell proliferation is coupled to perforin expression and is maintained in nonpro- gressors, Nat. Immunol., 3(11), 1061-1068, 2002.
52. Hunt, P.W., Martin, J.N., Sinclair, E., Bredt, B., Hagos, E., Lampiris, H., Deeks, S.G., T cell activation is associated with lower CD4+ T cell gains in human immunodeficiency virus-infected patients with sustained viral suppression during antiretroviral therapy, J. Infect. Dis., 187(10), 1534-1543, 2003.
53. Finkel, T.H., Tudor-Williams, G., Banda, N.K., Cotton, M.F., Curiel, T., Monks, C., Baba, T.W., Ruprecht, R.M., Kupfer, A., Apoptosis occurs predominantly in bystander cells and not in productively infected cells of HIV- and SIV-infected lymph nodes, Nat. Med., 1(2), 129-134, 1995.
54. 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(10), 5555-5566, 1995.
55. Benedict, C.A., Norris, P.S., and Ware, C.F., To kill or be killed: viral evasion of apoptosis, Nat. Immunol., 3(11), 1013-1018, 2002.
56. Estaquier, J., Idziorek, T., de Bels, F., Barre-Sinoussi, F., Hurtrel, B., Aubertin, A.M,. Venet, A., Mehtali, M., Muchmore, E., Michel, P., Programmed cell death and AIDS: significance of T-cell apoptosis in pathogenic and nonpathogenic primate lentiviral infections, Proc. Natl. Acad. Sci. U.S.A., 91(20), 9431-9435, 1994.
57. Gougeon, M.-L., Garcia, S., Heeney, J., Tschopp, R., Lecoeur, H., Guetard, D., Rame, V., Dauguet, C., Montagnier, L., Programmed cell death in AIDS-related HIV and SIV infections, AIDS Res. Hum. Retroviruses, 9(6), 553-563, 1993.
58. Gougeon, M.-L., Lecoeur, H., Boudet, F., Ledru, E., Marzabal, S., Boullier, S., Roue, R., Nagata, S., 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(6), 2964-2976, 1997.
59. Davis, I.C., Girard, M., and Fultz, P.N., Loss of CD4+ T cells in human immunodeficiency virus type 1-infected chimpanzees is associated with increased lymphocyte apoptosis, J. Virol., 72(6), 4623-4632, 1998.
60. Moretti, S., Marcellini, S., Boschini, A., Famularo, G., Santini, G., Alesse, E., Steinberg, S.M., Cifone, M.G., Kroemer, G., De Simone, C., Apoptosis and apoptosis-associated perturbations of peripheral blood lymphocytes during HIV infection: comparison between AIDS patients and asymptomatic longterm non-progressors, Clin. Exp. Immunol., 122(3), 364-373, 2000.
61. Lynch, D.H., Ramsdell, F., and Alderson, M.R., Fas and FasL in the homeostatic regulation of immune responses, Immunol. Today, 16(12), 569-574, 1995.
62. Suda, T., Okazaki, T., Naito, Y., Yokota, T., Arai, N., Ozaki, S., Nakao, K., Nagata, S., Expression of the Fas ligand in cells of T cell lineage, J. Immunol., 154(8), 3806-3813, 1995.
63. Kabelitz, D., Pohl, T., and Pechhold, K., T cell apoptosis triggered via the CD3/T cell receptor γ complex and alternative activation pathways, Curr. Top. Microbiol. Immunol., 200, 1-14, 1995.
64. Banda, N.K., Bernier, J., Kurahara, D.K., Kurrle, R., Haigwood, N., Sekaly, R.P., Finkel, T.H., Crosslinking CD4 by human immunodeficiency virus gp120 primes T cells for activation-induced apoptosis, J. Exp. Med., 176(4), 1099-1106, 1992.
65. Borthwick, N.J., Lowdell, M., Salmon, M., Akbar, A.N., Loss of CD28 expression on CD8(+) T cells is induced by IL-2 receptor γ-chain signalling cytokines and type I IFN, and increases susceptibility to activation-induced apoptosis, Int. Immunol., 12(7), 1005-1013, 2000.
66. Algeciras, A., Dockrell, D.H., Lynch, D.H., Paya, C.V., CD4 regulates susceptibility to Fas ligand- and tumor necrosis factor-mediated apoptosis, J. Exp. Med., 187(5), 711-720, 1998.
67. Debatin, K.M., Fahrig-Faissner, A., Enenkel-Stoodt, S,, Kreuz, W., Benner, A., Krammer, P.H., High expression of APO-1 (CD95) on T lymphocytes from human immunodeficiency virus-1-infected children, Blood, 83(10), 3101-3103, 1994.
68. Katsikis, P.D., Wunderlich, E.S., Smith, C.A., Herzenberg, L.A., Herzenberg, L.A., Fas antigen stimulation induces marked apoptosis of T lymphocytes in human immunodeficiency virus-infected individuals, J. Exp. Med., 181(6), 2029-2036, 1995.
69. Baumler, C.B., Bohler, T., Herr, I., Benner, A., Krammer, P.H., Debatin, K.M., Activation of the CD95 (APO-1/Fas) system in T cells from human immunodeficiency virus type-1-infected children, Blood, 88(5), 1741-1746, 1996.
70. McCloskey, T.W., Oyaizu, N., Bakshi, S., Kowalski, R., Kohn, N., Pahwa, S., CD95 expression and apoptosis during pediatric HIV infection: early upregulation of CD95 expression, Clin. Immunol. Immunopathol., 87(1), 33-41, 1998.
71. McCloskey, T.W., Oyaizu, N., Kaplan, M., Pahwa, S., Expression of the Fas antigen in patients infected with human immunodeficiency virus, Cytometry, 22(2), 111-114, 1995.
72. McCloskey, T.W., Bakshi, S., Than, S., Arman, P., Pahwa, S., Immunophenotypic analysis of peripheral blood mononuclear cells undergoing in vitro apoptosis after isolation from human immunodeficiency virus-infected children, Blood, 92(11), 4230-4237, 1998.
73. Oyaizu, N., McCloskey, T.W., Than, S., Hu, R., Kalyanaraman, V.S., Pahwa, S., Cross-linking of CD4 molecules upregulates Fas antigen expression in lymphocytes by inducing interferon- and tumor necrosis factor- secretion, Blood, 84(8), 2622-2631, 1994.
74. Desbarats, J., Freed, J.H., Campbell, P.A., Newell, M.K., Fas (CD95) expression and death-mediating function are induced by CD4 cross-linking on CD4+ T cells, Proc. Natl. Acad. Sci. U.S.A., 93(20), 11014-11018, 1996.
75. Agostini, C., Siviero, M., Facco, M., Carollo, D., Binotto, G., Tosoni, A., Cattelan, A.M., Zambello,
R., Trentin, L., Semenzato, G., Antiapoptotic effects of IL-15 on pulmonary Tc1 cells of patients with human immunodeficiency virus infection, Am. J. Respir. Crit. Care. Med., 163(2), 484-489, 2001.
76. Kalinkovich, A., Geleziunas, R., Kemper, O., Belenki, D., Wallach, D., Wainberg, M.A., Bentwich, Z., Increased soluble tumor necrosis factor receptor expression and release by human immunodeficiency virus type 1 infection, J. Interferon Cytokine Res., 15(9), 749-757, 1995.
77. Fackler, O.T. and Baur, A.S., Live and let die: Nef functions beyond HIV replication, Immunity, 16(4), 493-497, 2002.
78. Hestdal, K., Aukrust, P., Muller, F., Lien, E., Bjerkeli, V., Espevik, T., Froland, S.S., Dysregulation of membrane-bound tumor necrosis factor- and tumor necrosis factor receptors on mononuclear cells in human immunodeficiency virus type 1 infection: low percentage of p75-tumor necrosis factor receptor positive cells in patients with advanced disease and high viral load, Blood, 90(7), 2670-2679,
1997.
79. de Oliveira Pinto, L.M., Garcia, S., Lecoeur, H., Rapp, C., 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(5), 1666-1675,
2002.
80. Lahdevirta, J., Maury, C.P., Teppo, A.M., Repo, H., Elevated levels of circulating cachectin/tumor necrosis factor in patients with acquired immunodeficiency syndrome, Am. J. Med., 85(3), 289-291, 1988.
81. Stylianou, E., Bjerkeli, V., Yndestad, A., Heggelund, L., Waehre, T., Damas, J.K., Aukrust, P., Froland,
S. S., Raised serum levels of interleukin-18 is associated with disease progression and may contribute to virological treatment failure in HIV-1-infected patients, Clin. Exp. Immunol., 132(3), 462-466,
2003.
82. Zagury, D., Lachgar, A., Chams, V., Fall, L.S., Bernard, J., Zagury, J.F., Bizzini, B., Gringeri, A., Santagostino, E., Rappaport, J., Feldman, M., Burny, A., Gallo, R.C., Interferon- 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(7), 3851-3856, 1998.
83. Fanales-Belasio, E., Cafaro, A., Cara, A., Negri, D.R., Fiorelli, V., Butto, S., Moretti, S., Maggiorella, M.T., Baroncelli, S., Michelini, Z., Tripiciano, A., Sernicola, L., Scoglio, A., Borsetti, A., Ridolfi, B., Bona, R., Ten Haaft, P., Macchia, I., Leone, P., Pavone-Cossut, M.R., Nappi, F., Vardas, E., Magnani, M., Laguardia, E., Caputo, A., Titti, F., Ensoli, B., Native HIV-1 Tat protein targets monocyte-derived dendritic cells and enhances their maturation, function, and antigen-specific T cell responses, J. Immunol., 168(1), 197-206, 2002.
84. Huang, L., Bosch, I., Hofmann, W., Sodroski, J., Pardee, A.B., Tat protein induces human immunodeficiency virus type 1 (HIV-1) coreceptors and promotes infection with both macrophage-tropic and T-lymphotropic HIV-1 strains, J. Virol., 72(11), 8952-8960, 1998.
85. Zhang, M., Li, X., Pang, X., Ding, L., Wood, O., Clouse, K., Hewlett, I., 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(3), 290-296, 2001.
86. Yang, Y., Tikhonov, I., Ruckwardt, T.J., Djavani, M., Zapata, J.C., Pauza, C.D., 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(12), 6700-6708, 2003.
87. 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., Badley, A.D., Induction of cell death in human immunodeficiency virus-infected macrophages and resting memory CD4 T cells by TRAIL/Apo2l, J. Virol., 75(22), 11128-11136, 2001.
88. Oltvai, Z.N., Milliman, C.L., and Korsmeyer, S.J., Bcl-2 heterodimerizes in vivo with a conserved homolog, Bax, that accelerates programmed cell death, Cell, 74(4), 609-619, 1993.
89. Boudet, F., Lecoeur, H., and Gougeon, M.L., Apoptosis associated with ex vivo down-regulation of Bcl-2 and up-regulation of Fas in potential cytotoxic CD8+ T lymphocytes during HIV infection, J. Immunol., 156(6), 2282-2293, 1996.
90. Hashimoto, F., Oyaizu, N., Kalyanaraman, V.S., Pahwa, S., Modulation of Bcl-2 protein by CD4 cross-linking: a possible mechanism for lymphocyte apoptosis in human immunodeficiency virus infection and for rescue of apoptosis by interleukin-2, Blood, 90(2), 745-753, 1997.
91. Blair, PJ., Boise, L.H., Perfetto, S.P., Levine, B.L., McCrary, G., Wagner, K.F., St Louis, D.C., Thompson, C.B., Siegel, J.N., June, C.H., Impaired induction of the apoptosis-protective protein Bcl- xL in activated PBMC from asymptomatic HIV-infected individuals, J. Clin. Immunol., 17(3), 234-246, 1997.
92. Petrovas, C., Mueller, Y.M., Dimitriou, I.D., Bojczuk, P.M., Mounzer, K.C., Witek, J., Altman, J.D., Katsikis, P.D., HIV-specific CD8(+) T cells exhibit markedly reduced levels of Bcl-2 and Bcl-x(L), J. Immunol., 172(7), 4444-4453, 2004.
93. Somma, F., Tuosto, L., Gilardini Montani, M.S., Di Somma, M.M., Cundari, E., Piccolella, E., Engagement of CD4 before TCR triggering regulates both Bax- and Fas (CD95)-mediated apoptosis, J. Immunol., 164(10), 5078-5087, 2000.
94. Rizzardi, G.P., Harari, A., Capiluppi, B., Tambussi, G., Ellefsen, K., Ciuffreda, D., Champagne, P., Bart, P.A., Chave, J.P., Lazzarin, A., Pantaleo, G., Treatment of primary HIV-1 infection with cyclosporin A coupled with highly active antiretroviral therapy, J. Clin. Invest., 109(5), 681-688, 2002.
95. Garber, D.A., Silvestri, G., Barry, A.P., Fedanov, A., Kozyr, N., McClure, H., Montefiori, D.C., Larsen,
C. P., Altman, J.D., Staprans, S.I., Feinberg, M.B., Blockade of T cell costimulation reveals interrelated actions of CD4+ and CD8+ T cells in control of SIV replication, J. Clin. Invest., 113(6), 836-845, 2004.
96. Waldmann, T.A., Dubois, S., and Tagaya, Y., Contrasting roles of IL-2 and IL-15 in the life and death of lymphocytes: implications for immunotherapy, Immunity, 14(2), 105-110, 2001.
97. Regamey, N., Harr, T., Battegay, M., Erb, P., Downregulation of Bcl-2, but not of Bax or Bcl-x, is associated with T lymphocyte apoptosis in HIV infection and restored by antiretroviral therapy or by interleukin 2, AIDS Res. Hum. Retroviruses, 15(9), 803-810, 1999.
98. Adachi, Y., Oyaizu, N., Than, S., McCloskey, T.W., 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(9), 4184-4193, 1996.
99. Mueller, Y.M., Bojczuk, P.M., Halstead, E.S., Kim, A.H., Witek, J., Altman, J.D., Katsikis, P.D., IL- 15 enhances survival and function of HIV-specific CD8+ T cells, Blood, 101(3), 1024-1029, 2003.
100. Cruikshank, W.W., Lim, K., Theodore, A.C., Cook, J., Fine, G., Weller, P.F., Center, D.M., IL-16 inhibition of CD3-dependent lymphocyte activation and proliferation, J. Immunol., 157(12), 5240-5248, 1996.
101. Idziorek, T., Khalife, J., Billaut-Mulot, O., Hermann, E., Aumercier, M., Mouton, Y., Capron, A., Bahr, G.M., Recombinant human IL-16 inhibits HIV-1 replication and protects against activation- induced cell death (AICD), Clin. Exp. Immunol., 112(1), 84-91, 1998.
102. Badley, A.D., Parato, K., Cameron, D.W., Kravcik, S., Phenix, B.N., Ashby, D., Kumar, A., Lynch,
D. H., Tschopp, J., Angel, J.B., Dynamic correlation of apoptosis and immune activation during treatment of HIV infection, Cell Death Differ., 6(5), 420-432, 1999.
103. Chavan, S., Kodoth, S., Pahwa, R., Pahwa, S., The HIV protease inhibitor Indinavir inhibits cell-cycle progression in vitro in lymphocytes of HIV-infected and uninfected individuals, Blood, 98(2), 383-389, 2001.
104. Sloand, E.M., Kumar, P.N., Kim, S., Chaudhuri, A., Weichold, F.F., 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(3), 1021-1027, 1999.
105. Groux, H., Torpier, G., Monte, D., Mouton, Y., Capron, A., Ameisen JC., Activation-induced death by apoptosis in CD4+ T cells from human immunodeficiency virus-infected asymptomatic individuals, J. Exp. Med., 175(2), 331-340, 1992.
106. Yang, Y., Liu, Z.H., Ware, C.F., Ashwell, J.D., A cysteine protease inhibitor prevents activation-induced T-cell apoptosis and death of peripheral blood cells from human immunodeficiency virus-infected individuals by inhibiting upregulation of Fas ligand, Blood, 89(2), 550-557, 1997.
107. Yang, Y., Bailey, J., Vacchio, M.S., Yarchoan, R., Ashwell, J.D., Retinoic acid inhibition of ex vivo human immunodeficiency virus-associated apoptosis of peripheral blood cells, Proc. Natl. Acad. Sci. U.S.A., 92(7), 3051-3055, 1995.
108. Szondy, Z., Lecoeur, H., Fesus, L., 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(5), 1288-1298,
1998.
109. Pinto, L.A., Williams, M.S., Dolan, M.J., Henkart, P.A., Shearer, G.M., Beta-chemokines inhibit activation-induced death of lymphocytes from HIV-infected individuals, Eur. J. Immunol., 30(7), 2048-2055, 2000.
110. Roth, G., Moser, B., Krenn, C., Brunner, M., Haisjackl, M., Almer, G., Gerlitz, S., Wolner, E., Boltz- Nitulescu, G., Ankersmit, H.J., Susceptibility to programmed cell death in T-lymphocytes from septic patients: a mechanism for lymphopenia and Th2 predominance, Biochem. Biophys. Res. Commun., 308(4), 840-846, 2003.