CONCLUSiON

Although HAART has clearly brought about an enormous improvement in the survival rates of HIV-1-infected patients, it is clear that it does not completely eradicate the virus or completely restore immune responses.

REFERENCES

1. Akbar, A.N., Borthwick, N., Salmon, M., Gombert, W., Bofill, M., Shamsadeen, N., Pilling, D., Pett, S., Grundy, J.E., and Janossy, G., The significance of low Bcl-2 expression by CD45RO T cells in normal individuals and patients with acute viral infections. The role of apoptosis in T cell memory,

J. Exp. Med., 178, 427, 1993.

2. Steel, C.M., Ludlam, C.A., Beatson, D., Peutherer, J.F., Cuthbert, R.J., Simmonds, P., Morrison, H., and Jones, M., HLA haplotype A1 B8 DR3 as a risk factor for HIV-related disease, Lancet, 1, 1185, 1988.

3. Simmonds, P., Beatson, D., Cuthbert, R.J., Watson, H., Reynolds, B., Peutherer, J.F., Parry, J.V., Ludlam, C.A., and Steel, C.M., Determinants of HIV disease progression: six-year longitudinal study in the Edinburgh haemophilia/HIV cohort, Lancet, 338, 1159, 1991.

4. Ameisen, J.C.

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

6. 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.

7. 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.

8. Cossarizza, A., T-cell repertoire and HIV infection: facts and perspectives, AIDS, 11, 1075, 1997.

9. Cossarizza, A., Stent, G., Mussini, C., Paganelli, R., Borghi, V., Nuzzo, C., Pinti, M., Pedrazzi, J., Benatti, F., Esposito, R., Rosok, B., Nagata, S., Vella, S., Franceschi, C., and De Rienzo, B., Dereg­ulation of the CD95/CD95L system in lymphocytes from patients with primary acute HIV infection, AIDS, 14, 345, 2000.

10. Giorgi, J.V., Hultin, L.E., McKeating, J.A., Johnson, T.D., Owens, B., Jacobson, L.P., Shih, R., Lewis,

J., Wiley, D.J., Phair, J.P., Wolinsky, S.M., and Detels, R., Shorter survival in advanced human immunodeficiency virus type 1 infection is more closely associated with T lymphocyte activation than with plasma virus burden or virus chemokine coreceptor usage, J. Infect. Dis., 179, 859, 1999.

11. Zinkernagel, R.M. and Hengartner, H., T-cell-mediated immunopathology vs. direct cytolysis by virus: implications for HIV and AIDS, Immunol. Today, 15, 262, 1994.

12. Sousa, A.E., Carneiro, J., Meier-Schellersheim, M., Grossman, Z., and 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.

13. Hazenberg, M.D., Otto, S.A., van Benthem, B.H., Roos, M.T., Coutinho, R.A., Lange, J.M., Hamann, D., Prins, M., and Miedema, F., Persistent immune activation in HIV-1 infection is associated with progression to AIDS, AIDS, 17, 1881, 2003.

14. Sopper, S., Nierwetberg, D., Halbach, A., Sauer, U., Scheller, C., Stahl-Hennig, C., Matz-Rensing,

K., Schafer, F., Schneider, T., ter Meulen, V., and Muller, J.G., Impact of simian immunodeficiency virus (SIV) infection on lymphocyte numbers and T-cell turnover in different organs of rhesus monkeys, Blood, 101, 1213, 2003.

15. Cajigas, A., Suhrland, M., Harris, C., Chu, F., McGowan, J., Golodner, M., Seymour, A.W., and Lyman, W.D., Correlation of the ratio of CD4+/CD8+ cells in lymph node fine needle aspiration biopsies with HIV clinical status. A preliminary study, Acta Cytol., 41, 1762, 1997.

16. Tedla, N., Dwyer, J., Truskett, P., Taub, D., Wakefield, D., and Lloyd, A., Phenotypic and functional characterization of lymphocytes derived from normal and HIV-1-infected human lymph nodes, Clin. Exp. Immunol., 117, 92, 1999.

17. Pitcher, C.J., Quittner, C., Peterson, D.M., Connors, M., Koup, R.A., Maino, V.C., and Picker, L.J., HIV-1-specific CD4+ T cells are detectable in most individuals with active HIV-1 infection, but decline with prolonged viral suppression, Nat. Med., 5, 518, 1999.

18. Kaech, S.M., Wherry, E.J., and Ahmed, R., Effector and memory T-cell differentiation: implications for vaccine development, Nat. Rev. Immunol., 2, 251, 2002.

19. Tanchot, C., Barber, D.L., Chiodetti, L., and Schwartz, R.H., Adaptive tolerance of CD4+ T cells in vivo: multiple thresholds in response to a constant level of antigen presentation, J. Immunol., 167, 2030, 2001.

20. Roger, P.M., Durant, J., Ticchioni, M., Halfon, P., Breittmayer, J.P., Brignone, C., Chaillou, S., Dunais, B., Dellamonica, P., and Bernard, A., Apoptosis and proliferation kinetics of T cells in patients having experienced antiretroviral treatment interruptions, J.

21. Hess, C., Altfeld, M., Thomas, S.Y., Addo, M.M., Rosenberg, E.S., Allen, T.M., Draenert, R., Eldrige, R.L., van Lunzen, J., Stellbrink, H.J., Walker, B.D., and Luster, A.D., HIV-1 specific CD8+ T cells with an effector phenotype and control of viral replication, Lancet, 363, 863, 2004.

22. Cossarizza, A., Poccia, F., Agrati, C., D'Offizi, G., Bugarini, R., Pinti, M., Borghi, V., Mussini, C., Esposito, R., Ippolito, G., and Narciso, P., Highly active antiretroviral therapy restores CD4+ V T-cell repertoire in patients with primary acute HIV infection but not in treatment-naive HIV+ patients with severe chronic infection, J. Acquir. Immune Defic. Syndr., 35, 213, 2004.

23. Lawen, A., Apoptosis—an introduction, Bioessays, 25, 888, 2003.

24. Reed, J.C., Mechanisms of apoptosis, Am. J. Pathol., 157, 1415, 2000.

25. Rossi, D. and Gaidano, G., Messengers of cell death: apoptotic signaling in health and disease, Haematologica, 88, 212, 2003.

26. Yonehara, S., Ishii, A., and Yonehara, M., A cell-killing monoclonal antibody (anti-Fas) to a cell surface antigen co-downregulated with the receptor of tumor necrosis factor, J. Exp. Med., 169, 1747, 1989.

27. Trauth, B.C., Klas, C., Peters, A.M., Matzku, S., Moller, P., Falk, W., Debatin, K.M., and Krammer, P.H., Monoclonal antibody-mediated tumor regression by induction of apoptosis, Science, 245, 301, 1989.

28. Patki, A.H., Georges, D.L., and Lederman, M.M., CD4+-T-cell counts, spontaneous apoptosis, and Fas expression in peripheral blood mononuclear cells obtained from human immunodeficiency virus type 1-infected subjects, Clin. Diagn. Lab. Immunol., 4, 736, 1997.

29. Roger, P.M., Breittmayer, J.P., Durant, J., Sanderson, F., Ceppi, C., Brignone, C., Cua, E., Clevenbergh, P., Fuzibet, J.G., Pesce, A., Bernard, A., and Dellamonica, P., Early CD4(+) T cell recovery in human immunodeficiency virus-infected patients receiving effective therapy is related to a down-regulation of apoptosis and not to proliferation, J.

30. 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.

31. 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.

32. Pinti, M., Biswas, P., Troiano, L., Nasi, M., Ferraresi, R., Mussini, C., Vecchiet, J., Esposito, R., Paganelli, R., and Cossarizza, A., Different sensitivity to apoptosis in cells of monocytic or lympho­cytic origin chronically infected with human immunodeficiency virus type-1, Exp. Biol. Med., 228, 1346, 2003.

33. Phenix, B.N., Cooper, C., Owen, C., and Badley, A.D., Modulation of apoptosis by HIV protease inhibitors, Apoptosis, 7, 295, 2002.

34. Weichold, F.F., Bryant, J.L., Pati, S., Barabitskaya, O., Gallo, R.C., and Reitz, M.S., Jr., HIV-1 protease inhibitor ritonavir modulates susceptibility to apoptosis of uninfected T cells, J. Hum. Virol., 2, 261, 1999.

35. 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.

36. Sloand, E.M., Maciejewski, J., Kumar, P., Kim, S., Chaudhuri, A., and Young, N., Protease inhibitors stimulate hematopoiesis and decrease apoptosis and ICE expression in CD34(+) cells, Blood, 96, 2735, 2000.

37. 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.

38. Phenix, B.N., Lum, J.J., Nie, Z., Sanchez-Dardon, J., and Badley, A.D., Antiapoptotic mechanism of HIV protease inhibitors: preventing mitochondrial transmembrane potential loss, Blood, 98, 1078, 2001.

39. Chavan, S., Kodoth, S., Pahwa, R., and Pahwa, S., The HIV protease inhibitor Indinavir inhibits cell­cycle progression in vitro in lymphocytes of HIV-infected and uninfected individuals, Blood, 98, 383, 2001.

40. Cossarizza, A., Kalashnikova, G., Grassilli, E., Chiappelli, F., Salvioli, S., Capri, M., Barbieri, D., Troiano, L., Monti, D., and Franceschi, C., Mitochondrial modifications during rat thymocyte apop­tosis: a study at the single cell level, Exp. Cell Res., 214, 323, 1994.

41. Matarrese, P., Gambardella, L., Cassone, A., Vella, S., Cauda, R., and Malorni, W., Mitochondrial membrane hyperpolarization hijacks activated T lymphocytes toward the apoptotic-prone phenotype: homeostatic mechanisms of HIV protease inhibitors, J. Immunol., 170, 6006, 2003.

42. Lane, H.C., Depper, J.M., Greene, W.C., Whalen, G., Waldmann, T.A., and Fauci, A.S., Qualitative analysis of immune function in patients with the acquired immunodeficiency syndrome. Evidence for a selective defect in soluble antigen recognition, N. Engl. J. Med., 313, 79, 1985.

43. Wahren, B., Morfeldt-Mansson, L., Biberfeld, G., Moberg, L., Sonnerborg, A., Ljungman, P., Werner, A., Kurth, R., Gallo, R., and Bolognesi, D., Characteristics of the specific cell-mediated immune response in human immunodeficiency virus infection, J. Virol., 61, 2017, 1987.

44. Clerici, M., Stocks, N.I., Zajac, R.A., Boswell, R.N., Lucey, D.R., Via, C.S., and Shearer, G.M., Detection of three distinct patterns of T helper cell dysfunction in asymptomatic, human immunode­ficiency virus-seropositive patients. Independence of CD4+ cell numbers and clinical staging, J. Clin. Invest., 84, 1892, 1989.

45. Telander, D.G., Malvey, E.N., and Mueller, D.L., Evidence for repression of IL-2 gene activation in anergic T cells, J. Immunol., 162, 1460, 1999.

46. Mor, F. and Cohen, I.R., IL-2 rescues antigen-specific T cells from radiation or dexamethasone-induced apoptosis. Correlation with induction of Bcl-2, J. Immunol., 156, 515, 1996.

47. Shi, Y., Wang, R., Sharma, A., Gao, C., Collins, M., Penn, L., and Mills, G.B., Dissociation of cytokine signals for proliferation and apoptosis, J. Immunol., 159, 5318, 1997.

48. Homann, D., Teyton, L., and Oldstone, M.B., Differential regulation of antiviral T-cell immunity results in stable CD8+ but declining CD4+ T-cell memory, Nat. Med., 7, 913, 2001.

49. Grelli, S., D’Ettore, G., Lauria, F., Montella, F., Di Traglia, L., D’Agostini, C., Lichtner, M., Vullo, V., Favalli, C., Vella, S., Macchi, B., and Mastino, A., CD4+ lymphocyte increases in HIV patients during potent antiretroviral therapy are dependent on inhibition of CD8+ cell apoptosis, Ann. N.Y. Acad. Sci., 1010, 560, 2003.

50. Hansjee, N.E.A., Persistent apoptosis in HIV-1-infected individuals receiving potent antiretroviral therapy is associated with poor recovery of CD4 lymphocyes, J. Acquir. Immune Defic. Syndr., 36, 671, 2004.

51. 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/Apo2l, J. Virol., 75, 1128, 2001.

52. Roitt, I.M., Essential Immunology, 7th ed., Blackwell Scientific, Oxford, 1991, p. 141.

53. Mosmann, T.R., Cherwinski, H., Bond, M.W., Giedlin, M.A., and Coffman, R.L., Two types of murine helper T cell clone. I. Definition according to profiles of lymphokine activities and secreted proteins, J. Immunol., 136, 2348, 1986.

54. Paul, W.E. and Seder, R.A., Lymphocyte responses and cytokines, Cell, 76, 241, 1994.

55. Parish, C.R., The relationship between humoral and cell-mediated immunity, TransplantRev., 13, 35, 1972.

56. Clerici, M., Hakim, F.T., Venzon, D.J., Blatt, S., Hendrix, C.W., Wynn, T.A., and Shearer, G.M., Changes in interleukin-2 and interleukin-4 production in asymptomatic, human immunodeficiency virus-seropositive individuals, J. Clin. Invest., 91, 759, 1993.

57. Bloom, B.R., Salgame, P., and Diamond, B., Revisiting and revising suppressor T cells, Immunol. Today, 13, 131, 1992.

58. Clerici, M. and Shearer, G.M., The Th1-Th2 hypothesis of HIV infection: new insights, Immunol. Today, 15, 575, 1994.

59. Clerici, M. and Shearer, G.M., A TH1-->TH2 switch is a critical step in the etiology of HIV infection, Immunol. Today, 14, 107, 1993.

60. Clerici, M., Sarin, A., Coffman, R.L., Wynn, T.A., Blatt, S.P., Hendrix, C.W., Wolf, S.F., Shearer, G.M., and Henkart, P.A., Type 1/type 2 cytokine modulation of T-cell programmed cell death as a model for human immunodeficiency virus pathogenesis, Proc. Natl. Acad. Sci. U.S.A., 91, 11811, 1994.

61. Chun, T.W., Engel, D., Mizell, S.B., Hallahan, C.W., Fischette, M., Park, S., Davey, R.T., Jr., Dybul, M., Kovacs, J.A., Metcalf, J.A., Mican, J.M., Berrey, M.M., Corey, L., Lane, H.C., and Fauci, A.S., Effect of interleukin-2 on the pool of latently infected, resting CD4+ T cells in HIV-1-infected patients receiving highly active anti-retroviral therapy, Nat. Med., 5, 651, 1999.

62. Paiardini, M., Galati, D., Cervasi, B., Cannavo, G., Galluzzi, L., Montroni, M., Guetard, D., Magnani, M., Piedimonte, G., and Silvestri, G., Exogenous interleukin-2 administration corrects the cell cycle perturbation of lymphocytes from human immunodeficiency virus-infected individuals, J. Virol., 75, 10843, 2001.

63. NIH press release, NIAID News: IL-2 Increases CD4+ Cells, March 1995.

64. Zaunders, J.J., Moutouh-de Parseval, L., Kitada, S., Reed, J.C., Rought, S., Genini, D., Leoni, L., Kelleher, A., Cooper, D.A., Smith, D.E., Grey, P., Estaquier, J., Little, S., Richman, D.D., and Corbeil, J., Polyclonal proliferation and apoptosis of CCR5+ T lymphocytes during primary human immuno­deficiency virus type 1 infection: regulation by interleukin (IL)-2, IL-15, and Bcl-2, J. Infect. Dis., 187, 1735, 2003.

65. Reynes, J., Portales, P., Segondy, M., Baillat, V., Andre, P., Reant, B., Avinens, O., Couderc, G., Benkirane, M., Clot, J., Eliaou, J.F., and Corbeau, P., CD4+ T cell surface CCR5 density as a determining factor of virus load in persons infected with human immunodeficiency virus type 1, J. Infect. Dis., 181, 927, 2000.

66. Unutmaz, D., KewalRamani, V.N., Marmon, S., and Littman, D.R., Cytokine signals are sufficient for HIV-1 infection of resting human T lymphocytes, J. Exp. Med., 189, 1735, 1999.

67. Perera, L.P., Goldman, C.K., and Waldmann, T.A., IL-15 induces the expression of chemokines and their receptors in T lymphocytes, J. Immunol., 162, 2606, 1999.

68. Chapdelaine, Y., Smith, D.K., Pedras-Vasconcelos, J.A., Krishnan, L., and Sad, S., Increased CD8+ T cell memory to concurrent infection at the expense of increased erosion of pre-existing memory: the paradoxical role of IL-15, J. Immunol., 171, 5454, 2003.

69. Harari, A., Petitpierre, S., Vallelian, F., and Pantaleo, G., Skewed representation of functionally distinct populations of virus-specific CD4 T cells in HIV-1-infected subjects with progressive disease: changes after antiretroviral therapy, Blood, 103, 966, 2004.

70. Trinchieri, G., Interleukin-12: a cytokine produced by antigen-presenting cells with immunoregulatory functions in the generation of T-helper cells type 1 and cytotoxic lymphocytes, Blood, 84, 4008, 1994.

71. Spadaro, M., Lanzardo, S., Curcio, C., Forni, G., and Cavallo, F., Immunological inhibition of carcinogenesis, Cancer Immunol. Immunother., 53, 204, 2004.

72. Portielje, J.E., Gratama, J.W., van Ojik, H.H., Stoter, G., and Kruit, W.H., IL-12: a promising adjuvant for cancer vaccination, Cancer Immunol. Immunother., 52, 133, 2003.

73. Seaman, M.S., Peyerl, F.W., Jackson, S.S., Lifton, M.A., Gorgone, D.A., Schmitz, J.E., and Letvin, N.L., Subsets of memory cytotoxic T lymphocytes elicited by vaccination influence the efficiency of secondary expansion in vivo, J. Virol., 78, 206, 2004.

74. Napolitano, L.A., Stoddart, C.A., Hanley, M.B., Wieder, E., and McCune, J.M., Effects of IL-7 on early human thymocyte progenitor cells in vitro and in SCID-hu Thy/Liv mice, J. Immunol., 171, 645, 2003.

75. Pallard, C., Stegmann, A.P., van Kleffens, T., Smart, F., Venkitaraman, A., and Spits, H., Distinct roles of the phosphatidylinositol 3-kinase and STAT5 pathways in IL-7-mediated development of human thymocyte precursors, Immunity, 10, 525, 1999.

76. Steffens, C.M., Managlia, E.Z., Landay, A., and Al-Harthi, L., Interleukin-7-treated naive T cells can be productively infected by T-cell-adapted and primary isolates of human immunodeficiency virus 1, Blood, 99, 3310, 2002.

77. Mussini, C.., Pinti, M., Borghi, V., Nasi, M., Amorico, G., Monterastelli, E., Moretti, L., Troiano, L., Esposito, R., and Cossarizza, A, Features of “CD4-exploders,” HIV-positive patients with an optimal immune reconstitution after potent antiretroviral therapy, AIDS, 16, 1609, 2002.

78. Silvestri, G. and Feinberg, M.B., Turnover of lymphocytes and conceptual paradigms in HIV infection, J. Clin. Invest., 112, 821, 2003.

79. Roederer, M., Getting to the HAART of T cell dynamics, Nat. Med., 4, 145, 1998.

80. Haase, A.T., Population biology of HIV-1 infection: viral and CD4+ T cell demographics and dynamics in lymphatic tissues, Annu. Rev. Immunol., 17, 625, 1999.

81. McCune, J.M., The dynamics of CD4+ T-cell depletion in HIV disease, Nature, 410, 6831, 2001.

82. Grossman, Z., Meier-Schellersheim, M., Sousa, A.E., Victorino, R.M., and Paul, W.E., CD4+ T-cell depletion in HIV infection: are we closer to understanding the cause? Nat. Med., 8, 319, 2002.

83. Douek, D.C., McFarland, R.D., Keiser, P.H., Gage, E.A., Massey, J.M., Haynes, B.F., Polis, M.A., Haase, A.T., Feinberg, M.B., Sullivan, J.L., Jamieson, B.D., Zack, J.A., Picker, L.J., and Koup, R.A., Changes in thymic function with age and during the treatment of HIV infection, Nature, 396, 690, 1998.

84. Zack, J.A., Arrigo, S.J., Weitsman, S.R., Go, A.S., Haislip, A., and Chen, I.S., HIV-1 entry into quiescent primary lymphocytes: molecular analysis reveals a labile, latent viral structure, Cell, 61, 213, 1990.

85. Stevenson, M., Stanwick, T.L., Dempsey, M.P., and Lamonica, C.A., HIV-1 replication is controlled at the level of T cell activation and proviral integration, EMBO J., 9, 1551, 1990.

86. 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.

87. Lori, F., Hydroxyurea and HIV: 5 years later—from antiviral to immune-modulating effects, AIDS, 13, 1433, 1999.

88. Donehower, R.C., An overview of the clinical experience with hydroxyurea, Semin. Oncol., 19, 11, 1992.

89. Charache, S., Effect of hydroxyurea on the frequency of painful crises in sickle cell anemia. Investi­gators of the Multicenter Study of Hydroxyurea in Sickle Cell Anemia, N. Engl. J. Med., 332, 1317, 1995.

90. Lori, F., Malykh, A., Cara, A., Sun, D., Weinstein, J.N., Lisziewicz, J., and Gallo, R.C., Hydroxyurea as an inhibitor of human immunodeficiency virus-type 1 replication, Science, 266, 801, 1994.

91. Malley, S.D., Grange, J.M., Hamedi-Sangsari, F., and Vila, J.R., Suppression of HIV production in resting lymphocytes by combining didanosine and hydroxamate compounds, Lancet, 343, 1292, 1994.

92. Palmer, S., Shafer, R.W., and Merigan, T.C, Hydroxyurea enhances the activities of didanosine, 9-[2- (phosphonylmethoxy)ethyl]adenine, and 9-[2- (phosphonylmethoxy)propyl]adenine against drug-sus­ceptible and drug-resistant human immunodeficiency virus isolates, Antimicrob. Agents Chemother., 43, 2046, 1999.

93. Lori, F. and Lisziewicz, J., Hydroxyurea: mechanisms of HIV-1 inhibition, Antiviral Ther., 3, 25, 1998.

94. Gao, W.Y., Johns, D.G., Chokekuchai, S., and Mitsuya, H., Disparate actions of hydroxyurea in potentiation of purine and pyrimidine 2,3-dideoxynucleoside activities against replication of human immunodeficiency, Proc. Natl. Acad. Sci. U.S.A., 92, 8333, 1995.

95. Gao, W.Y., Cara, A., Gallo, R.C., and Lori, F., Low levels of deoxynucleotides in peripheral blood lymphocytes: a strategy to inhibit human immunodeficiency virus type 1 replication, Proc. Natl. Acad. Sci. U.S.A., 90, 8925, 1993.

96. Korin, Y.D. and Zack, J.A., Progression to the G1b phase of the cell cycle is required for completion of human immunodeficiency virus type 1 reverse transcription in T cells, J. Virol., 72, 3161, 1998.

97. Zagury, D., Bernard, J., Leonard, R., Cheynier, R., Feldman, M., Sarin, P.S., and Gallo, R.C., Long­term cultures of HTLV-III-infected T cells: a model of cytopathology of T-cell depletion in AIDS, Science, 231, 4740, 1986.

98. Heredia, A., Davis, C., Amoroso, A., Dominique, J.K., Le, N., Klingebiel, E., Reardon, E., Zella, D., and Redfield, R.R., Induction of G1 cycle arrest in T lymphocytes results in increased extracellular levels of -chemokines: a strategy to inhibit R5 HIV-1, Proc. Natl. Acad. Sci. U.S.A., 100, 4179, 2003.

99. Lori, F., Jessen, H., Lieberman, J., Clerici, M., Tinelli, C., and Lisziewicz, J., Immune restoration by combination of a cytostatic drug (hydroxyurea) and anti-HIV drugs (didanosine and indinavir), AIDS Res. Hum. Retroviruses, 15, 619, 1999.

100. Lori, F., Jessen, H., Lieberman, J., Finzi, D., Rosenberg, E., Tinelli, C., Walker, B., Siliciano, R.F., and Lisziewicz, J., Treatment of human immunodeficiency virus infection with hydroxyurea, didanosine, and a protease inhibitor before seroconversion is associated with normalized immune parameters and limited viral reservoir, J. Infect. Dis., 180, 1827, 1999.

101. Lori, F., Pollard, R.B., Whitman, L., Bakare, N., Blick, G., Shalit, P., Foli, A., Peterson, D., Tennenberg, A., Schrader, S., Rashbaum, B., Farthing, C., Herman, D., Norris, D., Greiger, P., Frank, I., Groff, A., Lova, L., Asmuth, D., and Lisziewicz, J., A Low Hydroxyurea Dose (600 mg Daily) Is Found Optimal in a Randomized, Controlled Trial (RIGHT 702), The XIV International AIDS Conference, Barcelona, July 7-12, 2002, Abstract #TuPeB446.

102. De Antoni, A., Mutations in the pol gene of human immunodeficiency virus type 1 in infected patients receiving didanosine and hydroxyurea combination therapy, J. Infect. Dis., 176, 899, 1997.

103. Gwilt, P.R. and Tracewell, W.G., Pharmacokinetics and pharmacodynamics of hydroxyurea, Clin. Pharmacokinet., 34, 347, 1998.

104. Colic, M., Stojic-Vukanic, Z., Pavlovic, B., Jandric, D., and Stefanoska, I, Mycophenolate mofetil inhibits differentiation, maturation and allostimulatory function of human monocyte-derived dendritic cells, Clin. Exp. Immunol., 134, 63, 2003.

105. Margolis, D., Heredia, A., Gaywee, J., Oldach, D., Drusano, G., and Redfield, R., Abacavir and mycophenolic acid, an inhibitor of inosine monophosphate dehydrogenase, have profound and syn­ergistic anti-HIV activity, J. Acquir. Immune Defic. Syndr., 21, 362, 1999.

106. Lui, S.L., Ramassar, V., Urmson, J., and Halloran, P.F, Mycophenolate mofetil reduces production of interferon-dependent major histocompatibility complex induction during allograft rejection, probably by limiting clonal expansion, Transpl. Immunol., 6, 23, 1998.

107. Konno, Y., Natsumeda, Y., Nagai, M., Yamaji, Y., Ohno, S., Suzuki, K., and Weber, G., Expression of human IMP dehydrogenase types I and II in Escherichia coli and distribution in human normal lymphocytes and leukemic cell lines, J. Biol. Chem., 266, 506, 1991.

108. Nagai, M., Natsumeda, Y., and Weber, G., Proliferation-linked regulation of type II IMP dehydrogenase gene in human normal lymphocytes and HL-60 leukemic cells, Cancer Res., 52, 258, 1992.

109. Allison, A.C. and Eugui, E.M., Mycophenolate mofetil and its mechanisms of action, Immunophar­macology, 47, 85, 2000.

110. Chapuis, A.G., Paolo Rizzardi, G., D’Agostino, C., Attinger, A., Knabenhans, C., Fleury, S., Acha- Orbea, H., and Pantaleo, G., Effects of mycophenolic acid on human immunodeficiency virus infection in vitro and in vivo, Nat. Med., 6, 762, 2000.

111. Ravot, E., Lisziewicz, J., and Lori, F., New uses for old drugs in HIV infection: the role of hydroxyurea, cyclosporin and thalidomide, Drugs, 58, 953, 1999.

112. Rizzardi, G.P., Harari, A., Capiluppi, B., Tambussi, G., Ellefsen, K., Ciuffreda, D., Champagne, P., Bart, P.A., Chave, J.P., Lazzarin, A., and Pantaleo, G., Treatment of primary HIV-1 infection with cyclosporin A coupled with highly active antiretroviral therapy, J. Clin. Invest., 109, 681, 2002.

113. Takahashi, K., Reynolds, M., Ogawa, N., Longo, D.L., and Burdick, J, Augmentation of T-cell apoptosis by immunosuppressive agents, Clin. Transplant, 18, 72, 2004.