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summary and future perspectives

A wide variety of organ culture and animal models has been developed to study HIV-1 replication and the pathogenesis of AIDS. Apoptosis induced by HIV-1 among infected and bystander cells is an important component of the pathogenic process that leads to AIDS after HIV-1 infection.

Animal and organ culture models play an important role in these studies, because they most closely mimic natural infection by HIV-1. Molecular pathways of apoptosis can be studied in cell lines, but their relevance to AIDS must be verified with more realistic models and, if possible, with cells or tissues from HIV-1-infected people.

Animal and organ culture models can also be used to test treatments for AIDS, including immune reconstitution and gene therapy. Thus, it will be interesting to see whether IL-7 treatment of HIV-1-infected FTOCs can protect ITTPs from HIV-1-mediated killing and enhance de novo naive T cell generation. Hematopoietic progenitor cells could be transduced with anti-HIV-1 or antiapoptotic genes and used to colonize FTOC or SCID-hu mice in order to check their effects on destructive events associated with HIV-1 infection of the thymus. Previous work has shown that transduction of human CD34+ cells with anti-HIV-1 genes inhibits HIV-1 replication in monocytes and lymphocytes produced in vitro.204-209 Animal and organ culture models will continue to be vital for the study of HIV-1-mediated apoptosis and its prevention.

REFERENCES

1. Jamieson, B.D., Douek, D.C., Killian, S., Hultin, L.E., Scripture-Adams, D.D., Giorgi, J.V., Marelli, D., Koup, R.A., and Zack, J.A., Generation of functional thymocytes in the human adult, Immunity, 10 (5), 569-575, 1999.

2. Poulin, J.F., Viswanathan, M.N., Harris, J.M., Komanduri, K.V., Wieder, E., Ringuette, N., Jenkins, M., McCune, J.M., and Sekaly, R.P., Direct evidence for thymic function in adult humans, J.

Exp. Med., 190 (4), 479-486, 1999.

3. Rosenzweig, M., Clark, D.P., and Gaulton, G.N., Selective thymocyte depletion in neonatal HIV-1 thymic infection, AIDS, 7 (12), 1601-1605, 1993.

4. Gaulton, G.N., Scobie, J.V., and Rosenzweig, M., HIV-1 and the thymus, AIDS, 11 (4), 403-414, 1997.

5. Douek, D.C., Koup, R.A., McFarland, R.D., Sullivan, J.L., and Luzuriaga, K., Effect of HIV on thymic function before and after antiretroviral therapy in children, J. Infect. Dis., 181 (4), 1479-1482, 2000.

6. 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 (6712), 690-695, 1998.

7. Kourtis, A.P., Ibegbu, C., Nahmias, A.J., Lee, F.K., Clark, W.S., Sawyer, M.K., and Nesheim, S., Early progression of disease in HIV-infected infants with thymus dysfunction, N. Engl. J. Med., 335 (19), 1431-1436, 1996.

8. Nahmias, A.J., Clark, W.S., Kourtis, A.P., Lee, F.K., Cotsonis, G., Ibegbu, C., Thea, D., Palumbo, P., Vink, P., Simonds, R.J., and Nesheim, S.R., Thymic dysfunction and time of infection predict mortality in human immunodeficiency virus-infected infants. CDC Perinatal AIDS Collaborative Transmission Study Group, J. Infect. Dis., 178 (3), 680-685, 1998.

9. Kalayjian, R.C., Landay, A., Pollard, R.B., Taub, D.D., Gross, B.H., Francis, I.R., Sevin, A., Pu, M., Spritzler, J., Chernoff, M., Namkung, A., Fox, L., Martinez, A., Waterman, K., Fiscus, S.A., Sha, B., Johnson, D., Slater, S., Rousseau, F., and Lederman, M.M., Age-related immune dysfunction in health and in human immunodeficiency virus (HIV) disease: association of age and HIV infection with naive CD8+ cell depletion, reduced expression of CD28 on CD8+ cells, and reduced thymic volumes, J. Infect. Dis., 187 (12), 1924-1933, 2003.

10. Vigano, A., Vella, S., Saresella, M., Vanzulli, A., Bricalli, D., Di Fabio, S., Ferrante, P., Andreotti, M., Pirillo, M., Dally, L.G., Clerici, M., and Principi, N., Early immune reconstitution after potent antiretroviral therapy in HIV-infected children correlates with the increase in thymus volume, AIDS, 14 (3), 251-261, 2000.

11. Knutsen, A.P., Roodman, S.T., Freeman, J.J., Mueller, K.R., and Bouhasin, J.D., Inhibition of thy- mopoiesis of CD34+ cell maturation by HIV-1 in an in vitro CD34+ cell and thymic epithelial organ culture model, Stem Cells, 17 (6), 327-338, 1999.

12. 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 (7), 779-789, 1999.

13. Ye, P., Kourtis, A.P., and Kirschner, D.E., Reconstitution of thymic function in HIV-1 patients treated with highly active antiretroviral therapy, Clin. Immunol., 106 (2), 95-105, 2003.

14. Su, L., Kaneshima, H., Bonyhadi, M., Salimi, S., Kraft, D., Rabin, L., and McCune, J.M., HIV-1- induced thymocyte depletion is associated with indirect cytopathogenicity and infection of progenitor cells in vivo, Immunity, 2 (1), 25-36, 1995.

15. Bonyhadi, M.L., Su, L., Auten, J., McCune, J.M., and Kaneshima, H., Development of a human thymic organ culture model for the study of HIV pathogenesis, AIDS Res. Hum. Retroviruses, 11 (9), 1073-1080, 1995.

16. Camerini, D., Su, H.P., Gamez-Torre, G., Johnson, M.L., Zack, J.A., and Chen, I.S., Human immu­nodeficiency virus type 1 pathogenesis in SCID-hu mice correlates with syncytium-inducing pheno­type and viral replication, J. Virol., 74 (7), 3196-3204, 2000.

17. Scoggins, R.M., Taylor, J.R., Jr., Patrie, J., van't Wout, A.B., Schuitemaker, H., and Camerini, D., Pathogenesis of primary R5 human immunodeficiency virus type 1 clones in SCID-hu mice, J. Virol., 74 (7), 3205-3216, 2000.

18. Bonyhadi, M.L., Rabin, L., Salimi, S., Brown, D.A., Kosek, J., McCune, J.M., and Kaneshima, H., HIV induces thymus depletion in vivo, Nature, 363 (6431), 728-732, 1993.

19. Rosenzweig, M., Bunting, E.M., and Gaulton, G.N., Neonatal HIV-1 thymic infection, Leukemia, 8 (Suppl. 1), S163-S165, 1994.

20. Rosenzweig, M., Bunting, E.M., Damico, R.L., Clark, D.P., and Gaulton, G.N., Human neonatal thymic organ culture: an ex vivo model of thymocyte ontogeny and HIV-1 infection, Pathobiology, 62 (5-6), 245-251, 1994.

21. Duus, K.M., Miller, E.D., Smith, J.A., Kovalev, G.I., and Su, L., Separation of human immunodefi­ciency virus type 1 replication from Nef-mediated pathogenesis in the human thymus, J. Virol., 75 (8), 3916-3924, 2001.

22. Keir, M.E., Rosenberg, M.G., Sandberg, J.K., Jordan, K.A., Wiznia, A., Nixon, D.F., Stoddart, C.A., and McCune, J.M., Generation of CD3+CD8low thymocytes in the HIV type 1-infected thymus, J. Immunol., 169 (5), 2788-2796, 2002.

23. Keir, M.E., Stoddart, C.A., Linquist-Stepps, V., Moreno, M.E., and McCune, J.M., IFN- secretion by type 2 predendritic cells up-regulates MHC class I in the HIV-1-infected thymus, J. Immunol., 168 (1), 325-331, 2002.

24. Miller, E.D., Duus, K.M., Townsend, M., Yi, Y., Collman, R., Reitz, M., and Su, L., Human immun­odeficiency virus type 1 IIIB selected for replication in vivo exhibits increased envelope glycoproteins in virions without alteration in coreceptor usage: separation of in vivo replication from macrophage tropism, J. Virol., 75 (18), 8498-8506, 2001.

25. Choudhary, S.K., Choudhary, N.R., Kimbrell, K.C., Colasanti, J., Ziogas, A., Kwa, D., Schuitemaker,

H., and Camerini, D., R5 HIV-1 infection of fetal thymic organ culture induces cytokine and CCR5 expression, J. Virol., 79 (1), 458-471, 2005.

26. Stoddart, C.A., Liegler, T.J., Mammano, F., Linquist-Stepps, V.D., Hayden, M.S., Deeks, S.G., Grant, R.M., Clavel, F., and McCune, J.M., Impaired replication of protease inhibitor-resistant HIV-1 in human thymus, Nat. Med., 7 (6), 712-718, 2001.

27. Finnegan, A., Roebuck, K.A., Nakai, B.E., Gu, D.S., Rabbi, M.F., Song, S., and Landay, A.L., IL- 10 cooperates with TNF- to activate HIV-1 from latently and acutely infected cells of monocyte/ macrophage lineage, J. Immunol., 156 (2), 841-851, 1996.

28. Kekow, J., Wachsman, W., McCutchan, J.A., Cronin, M., Carson, D.A., and Lotz, M., Transforming growth factor and noncytopathic mechanisms of immunodeficiency in human immunodeficiency virus infection, Proc.

Natl. Acad. Sci. U.S.A., 87 (21), 8321-8325, 1990.

29. Kolb, S.A., Sporer, B., Lahrtz, F., Koedel, U., Pfister, H.W., and Fontana, A., Identification of a T cell chemotactic factor in the cerebrospinal fluid of HIV-1-infected individuals as interferon- inducible protein 10, J. Neuroimmunol., 93 (1-2), 172-181, 1999.

30. Ostrowski, M.A., Gu, J.X., Kovacs, C., Freedman, J., Luscher, M.A., and MacDonald, K.S., Quanti­tative and qualitative assessment of human immunodeficiency virus type 1 (HIV-1)-specific CD4+ T cell immunity to Gag in HIV-1-infected individuals with differential disease progression: reciprocal interferon- and interleukin-10 responses, J. Infect. Dis., 184 (10), 1268-1278, 2001.

31. Kovalev, G., Duus, K., Wang, L., Lee, R., Bonyhadi, M., Ho, D., McCune, J.M., Kaneshima, H., and Su, L., Induction of MHC class I expression on immature thymocytes in HIV-1-infected SCID-hu Thy/Liv mice: evidence of indirect mechanisms, J. Immunol., 162 (12), 7555-7562, 1999.

32. Miller, E.D., Smith, J.A., Lichtinger, M., Wang, L., and Su, L., Activation of the signal transducer and activator of transcription 1 signaling pathway in thymocytes from HIV-1-infected human thymus, AIDS, 17 (9), 1269-1277, 2003.

33. Jamieson, B.D., Uittenbogaart, C.H., Schmid, I., and Zack, J.A., High viral burden and rapid CD4+ cell depletion in human immunodeficiency virus type 1-infected SCID-hu mice suggest direct viral killing of thymocytes in vivo, J. Virol., 71 (11), 8245-8253, 1997.

34. Stanley, S.K., McCune, J.M., Kaneshima, H., Justement, J.S., Sullivan, M., Boone, E., Baseler, M., Adelsberger, J., Bonyhadi, M., Orenstein, J., Fox, C.H., and Fauci, A.S., Human immunodeficiency virus infection of the human thymus and disruption of the thymic microenvironment in the SCID-hu mouse, J. Exp. Med., 178 (4), 1151-1163, 1993.

35. Verhasselt, B., Naessens, E., Verhofstede, C., De Smedt, M., Schollen, S., Kerre, T., Vanhecke, D., and Plum, J., Human immunodeficiency virus Nef gene expression affects generation and function of human T cells, but not dendritic cells, Blood, 94 (8), 2809-2818, 1999.

36. Nielsen, S.D., Jeppesen, D.L., Kolte, L., Clark, D.R., Sorensen, T.U., Dreves, A.M., Ersboll, A.K., Ryder, L.P., Valerius, N.H., and Nielsen, J.O., Impaired progenitor cell function in HIV-negative infants of HIV-positive mothers results in decreased thymic output and low CD4 counts, Blood, 98 (2), 398-404, 2001.

37. Berkowitz, R.D., Beckerman, K.P., Schall, T.J., and McCune, J.M., CXCR4 and CCR5 expression delineates targets for HIV-1 disruption of T cell differentiation, J. Immunol., 161 (7), 3702-3710, 1998.

38. von Freeden-Jeffry, U., Solvason, N., Howard, M., and Murray, R., The earliest T lineage-committed cells depend on IL-7 for Bcl-2 expression and normal cell cycle progression, Immunity, 7 (1), 147-154, 1997.

39. Murray, R., Suda, T., Wrighton, N., Lee, F., and Zlotnik, A., IL-7 is a growth and maintenance factor for mature and immature thymocyte subsets, Int. Immunol., 1 (5), 526-531, 1989.

40. Peschon, J.J., Morrissey, PJ., Grabstein, K.H., Ramsdell, F.J., Maraskovsky, E., Gliniak, B.C., Park,

L. S., Ziegler, S.F., Williams, D.E., Ware, C.B., Meyer, J.D., and Davison, B.L., Early lymphocyte expansion is severely impaired in interleukin 7 receptor-deficient mice, J. Exp. Med., 180 (5), 1955-1960, 1994.

41. 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 (2), 645-654, 2003.

42. Okamoto, Y., Douek, D.C., McFarland, R.D., and Koup, R.A., Effects of exogenous interleukin-7 on human thymus function, Blood, 99 (8), 2851-2858, 2002.

43. Levy, J.A., Pathogenesis of human immunodeficiency virus infection, Microbiol. Rev., 57 (1), 183-289, 1993.

44. Stebbing, J., Gazzard, B., and Douek, D.C., Where does HIV live? N. Engl. J. Med., 350 (18), 1872-1880, 2004.

45. Douek, D.C., Picker, L.J., and Koup, R.A., T cell dynamics in HIV-1 infection, Annu. Rev. Immunol., 21, 265-304, 2003.

46. Brenchley, J.M., Schacker, T.W., Ruff, L.E., Price, D.A., Taylor, J.H., Beilman, G.J., Nguyen, P.L., Khoruts, A., Larson, M., Haase, A.T., and Douek, D.C., CD4+ T cell depletion during all stages of HIV disease occurs predominantly in the gastrointestinal tract, J. Exp. Med., 200 (6), 749-759, 2004.

47. Veazey, R.S., DeMaria, M., Chalifoux, L.V., Shvetz, D.E., Pauley, D.R., Knight, H.L., Rosenzweig,

M., Johnson, R.P., Desrosiers, R.C., and Lackner, A.A., Gastrointestinal tract as a major site of CD4+ T cell depletion and viral replication in SIV infection, Science, 280 (5362), 427-431, 1998.

48. Guadalupe, M., Reay, E., Sankaran, S., Prindiville, T., Flamm, J., McNeil, A., and Dandekar, S., Severe CD4+ T-cell depletion in gut lymphoid tissue during primary human immunodeficiency virus type 1 infection and substantial delay in restoration following highly active antiretroviral therapy, J. Virol., 77 (21), 11708-11717, 2003.

49. Schacker, T., Little, S., Connick, E., Gebhard, K., Zhang, Z.Q., Krieger, J., Pryor, J., Havlir, D., Wong,

J.K., Schooley, R.T., Richman, D., Corey, L., and Haase, A.T., Productive infection of T cells in lymphoid tissues during primary and early human immunodeficiency virus infection, J. Infect. Dis., 183 (4), 555-562, 2001.

50. Pantaleo, G., Graziosi, C., Demarest, J.F., Butini, L., Montroni, M., Fox, C.H., Orenstein, J.M., Kotler, D.P., and Fauci, A.S., HIV infection is active and progressive in lymphoid tissue during the clinically latent stage of disease, Nature, 362 (6418), 355-358, 1993.

51. Embretson, J., Zupancic, M., Ribas, J.L., Burke, A., Racz, P., Tenner-Racz, K., and Haase, A.T., Massive covert infection of helper T lymphocytes and macrophages by HIV during the incubation period of AIDS, Nature, 362 (6418), 359-362, 1993.

52. Haase, A.T., Population biology of HIV-1 infection: viral and CD4+ T cell demographics and dynamics in lymphatic tissues, Annu. Rev. Immunol., 17, 625-656, 1999.

53. Heath, S.L., Tew, J.G., Szakal, A.K., and Burton, G.F., Follicular dendritic cells and human immuno­deficiency virus infectivity, Nature, 377 (6551), 740-744, 1995.

54. Spiegel, H., Herbst, H., Niedobitek, G., Foss, H.D., and Stein, H., Follicular dendritic cells are a major reservoir for human immunodeficiency virus type 1 in lymphoid tissues facilitating infection of CD4+ T-helper cells, Am. J. Pathol., 140 (1), 15-22, 1992.

55. Schacker, T.W., Nguyen, P.L., Beilman, G.J., Wolinsky, S., Larson, M., Reilly, C., and Haase, A.T., Collagen deposition in HIV-1 infected lymphatic tissues and T cell homeostasis, J. Clin. Invest., 110

(8), 1133-1139, 2002.

56. 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.

57. Zhang, Z.Q., Notermans, D.W., Sedgewick, G., Cavert, W., Wietgrefe, S., Zupancic, M., Gebhard,

K., Henry, K., Boies, L., Chen, Z., Jenkins, M., Mills, R., McDade, H., Goodwin, C., Schuwirth, C.M., Danner, S.A., and Haase, A.T., Kinetics of CD4+ T cell repopulation of lymphoid tissues after treatment of HIV-1 infection, Proc. Natl. Acad. Sci. U.S.A., 95 (3), 1154-1159, 1998.

58. 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 (2), 129-134, 1995.

59. Wang, L., Robb, C.W., and Cloyd, M.W., HIV induces homing of resting T lymphocytes to lymph nodes, Virology, 228 (2), 141-152, 1997.

60. 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 (1), 268-276, 1999.

61. 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 (2), 271-278, 2002.

62. Glushakova, S., Baibakov, B., Margolis, L.B., and Zimmerberg, J., Infection of human tonsil histo- cultures: a model for HIV pathogenesis, Nat. Med., 1 (12), 1320-1322, 1995.

63. Glushakova, S., Baibakov, B., Zimmerberg, J., and Margolis, L.B., Experimental HIV infection of human lymphoid tissue: correlation of CD4+ T cell depletion and virus syncytium-inducing/non- syncytium-inducing phenotype in histocultures inoculated with laboratory strains and patient isolates of HIV type 1, AIDS Res. Hum. Retroviruses, 13 (6), 461-471, 1997.

64. Schramm, B., Penn, M.L., Speck, R.F., Chan, S.Y., De Clercq, E., Schols, D., Connor, R.I., and Goldsmith, M.A., Viral entry through CXCR4 is a pathogenic factor and therapeutic target in human immunodeficiency virus type 1 disease, J. Virol., 74 (1), 184-192, 2000.

65. Blauvelt, A., Glushakova, S., and Margolis, L.B., HIV-infected human Langerhans cells transmit infection to human lymphoid tissue ex vivo, AIDS, 14 (6), 647-651, 2000.

66. Eckstein, D.A., Penn, M.L., Korin, Y.D., Scripture-Adams, D.D., Zack, J.A., Kreisberg, J.F., Roederer, M., Sherman, M.P., Chin, P.S., and Goldsmith, M.A., HIV-1 actively replicates in naive CD4(+) T cells residing within human lymphoid tissues, Immunity, 15 (4), 671-682, 2001.

67. Eckstein, D.A., Sherman, M.P., Penn, M.L., Chin, P.S., De Noronha, C.M., Greene, W.C., and Goldsmith, M.A., HIV-1 Vpr enhances viral burden by facilitating infection of tissue macrophages but not nondividing CD4+ T cells, J. Exp. Med., 194 (10), 1407-1419, 2001.

68. Glushakova, S., Grivel, J.C., Suryanarayana, K., Meylan, P., Lifson, J.D., Desrosiers, R., and Margolis,

L., Nef enhances human immunodeficiency virus replication and responsiveness to interleukin-2 in human lymphoid tissue ex vivo, J. Virol., 73 (5), 3968-3974, 1999.

69. Glushakova, S., Munch, J., Carl, S., Greenough, T.C., Sullivan, J.L., Margolis, L., and Kirchhoff, F., CD4 down-modulation by human immunodeficiency virus type 1 Nef correlates with the efficiency of viral replication and with CD4(+) T-cell depletion in human lymphoid tissue ex vivo, J. Virol., 75 (21), 10113-10117, 2001.

70. Glushakova, S., Grivel, J.C., Fitzgerald, W., Sylwester, A., Zimmerberg, J., and Margolis, L.B., Evidence for the HIV-1 phenotype switch as a causal factor in acquired immunodeficiency, Nat. Med., 4 (3), 346-349, 1998.

71. Kreisberg, J.F., Kwa, D., Schramm, B., Trautner, V., Connor, R., Schuitemaker, H., Mullins, J.I., van't Wout, A.B., and Goldsmith, M.A., Cytopathicity of human immunodeficiency virus type 1 primary isolates depends on coreceptor usage and not patient disease status, J. Virol., 75 (18), 8842-8847, 2001.

72. Fitzgerald, W., Sylwester, A.W., Grivel, J.C., Lifson, J.D., and Margolis, L.B., Noninfectious X4 but not R5 human immunodeficiency virus type 1 virions inhibit humoral immune responses in human lymphoid tissue ex vivo, J. Virol., 78 (13), 7061-7068, 2004.

73. Grivel, J.C. and Margolis, L.B., CCR5- and CXCR4-tropic HIV-1 are equally cytopathic for their T-cell targets in human lymphoid tissue, Nat. Med., 5 (3), 344-346, 1999.

74. Grivel, J.C., Malkevitch, N., and Margolis, L., Human immunodeficiency virus type 1 induces apo­ptosis in CD4(+) but not in CD8(+) T cells in ex vivo-infected human lymphoid tissue, J. Virol., 74 (17), 8077-8084, 2000.

75. Grivel, J.C., Biancotto, A., Ito, Y., Lima, R.G., and Margolis, L.B., Bystander CD4+ T lymphocytes survive in HIV-infected human lymphoid tissue, AIDS Res. Hum. Retroviruses, 19 (3), 211-216, 2003.

76. Jekle, A., Keppler, O.T., De Clercq, E., Schols, D., Weinstein, M., and Goldsmith, M.A., In vivo evolution of human immunodeficiency virus type 1 toward increased pathogenicity through CXCR4- mediated killing of uninfected CD4 T cells, J. Virol., 77 (10), 5846-5854, 2003.

77. 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 (9), 4541-4551, 2004.

78. Perfettini, J.L., Roumier, T., Castedo, M., Larochette, N., Boya, P., Raynal, B., Lazar, V., Ciccosanti,

F., Nardacci, R., Penninger, J., Piacentini, M., and Kroemer, G., NF-B and p53 are the dominant apoptosis-inducing transcription factors elicited by the HIV-1 envelope, J. Exp. Med., 199 (5), 629-640, 2004.

79. McCune, J., Kaneshima, H., Krowka, J., Namikawa, R., Outzen, H., Peault, B., Rabin, L., Shih, C.C., Yee, E., Lieberman, M., Weissman, I., and Shultz, L., The SCID-hu mouse: a small animal model for HIV infection and pathogenesis, Annu. Rev. Immunol., 9, 399-429, 1991.

80. Kaneshima, H., Su, L., Bonyhadi, M.L., Connor, R.I., Ho, D.D., and McCune, J.M., Rapid-high, syncytium-inducing isolates of human immunodeficiency virus type 1 induce cytopathicity in the human thymus of the SCID-hu mouse, J. Virol., 68 (12), 8188-8192, 1994.

81. Kitchen, S.G. and Zack, J.A., CXCR4 expression during lymphopoiesis: implications for human immunodeficiency virus type 1 infection of the thymus, J. Virol., 71 (9), 6928-6934, 1997.

82. Aldrovandi, G.M., Feuer, G., Gao, L., Jamieson, B., Kristeva, M., Chen, I.S., and Zack, J.A., The SCID-hu mouse as a model for HIV-1 infection, Nature, 363 (6431), 732-736, 1993.

83. Su, L., Kaneshima, H., Bonyhadi, M.L., Lee, R., Auten, J., Wolf, A., Du, B., Rabin, L., Hahn, B.H., Terwilliger, E., and McCune, J.M., Identification of HIV-1 determinants for replication in vivo, Virology, 227 (1), 45-52, 1997.

84. Aldrovandi, G.M. and Zack, J.A., Replication and pathogenicity of human immunodeficiency virus type 1 accessory gene mutants in SCID-hu mice, J. Virol., 70 (3), 1505-1511, 1996.

85. Berkowitz, R.D., Alexander, S., Bare, C., Linquist-Stepps, V., Bogan, M., Moreno, M.E., Gibson, L., Wieder, E.D., Kosek, J., Stoddart, C.A., and McCune, J.M., CCR5- and CXCR4-utilizing strains of human immunodeficiency virus type 1 exhibit differential tropism and pathogenesis in vivo, J. Virol., 72 (12), 10108-10117, 1998.

86. Jenkins, M., Hanley, M.B., Moreno, M.B., Wieder, E., and McCune, J.M., Human immunodeficiency virus-1 infection interrupts thymopoiesis and multilineage hematopoiesis in vivo, Blood, 91 (8), 2672-2678, 1998.

87. Koka, P.S., Fraser, J.K., Bryson, Y., Bristol, G.C., Aldrovandi, G.M., Daar, E.S., and Zack, J.A., Human immunodeficiency virus inhibits multilineage hematopoiesis in vivo, J. Virol., 72 (6), 5121-5127, 1998.

88. Joshi, V.V. and Oleske, J.M., Pathologic appraisal of the thymus gland in acquired immunodeficiency syndrome in children. A study of four cases and a review of the literature, Arch. Pathol. Lab. Med., 109 (2), 142-146, 1985.

89. Schulz, R. and Mellor, A.L., Self major histocompatibility complex class I antigens expressed solely in lymphoid cells do not induce tolerance in the CD4+ T cell compartment, J. Exp. Med., 184 (4), 1573-1578, 1996.

90. Zaitseva, M., Kawamura, T., Loomis, R., Goldstein, H., Blauvelt, A., and Golding, H., Stromal-derived factor 1 expression in the human thymus, J. Immunol., 168 (6), 2609-2617, 2002.

91. Jenkins, M., Keir, M., and McCune, J.M., Fas is expressed early in human thymocyte development but does not transmit an apoptotic signal, J. Immunol., 163 (3), 1195-1204, 1999.

92. Jenkins, M., Keir, M., and McCune, J.M., A membrane-bound Fas decoy receptor expressed by human thymocytes, J. Biol. Chem., 275 (11), 7988-7993, 2000.

93. Lenardo, M.J., Angleman, S.B., Bounkeua, V., Dimas, J., Duvall, M.G., Graubard, M.B., Hornung, F., Selkirk, M.C., Speirs, C.K., Trageser, C., Orenstein, J.O., and Bolton, D.L., Cytopathic killing of peripheral blood CD4(+) T lymphocytes by human immunodeficiency virus type 1 appears necrotic rather than apoptotic and does not require Env, J. Virol., 76 (10), 5082-5093, 2002.

94. Bolton, D.L., Hahn, B.I., Park, E.A., Lehnhoff, L.L., Hornung, F., and Lenardo, M.J., Death of CD4(+) T-cell lines caused by human immunodeficiency virus type 1 does not depend on caspases or apoptosis, J. Virol., 76 (10), 5094-5107, 2002.

95. 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 (3), 1566-1578, 2003.

96. Ricci, J.E., Munoz-Pinedo, C., Fitzgerald, P., Bailly-Maitre, B., Perkins, G.A., Yadava, N., Scheffler,

I. E., Ellisman, M.H., and Green, D.R., Disruption of mitochondrial function during apoptosis is mediated by caspase cleavage of the p75 subunit of complex I of the electron transport chain, Cell, 117 (6), 773-786, 2004.

97. Ricci, J.E., Gottlieb, R.A., and Green, D.R., Caspase-mediated loss of mitochondrial function and generation of reactive oxygen species during apoptosis, J. Cell Biol., 160 (1), 65-75, 2003.

98. Mosier, D.E., Gulizia, R.J., Baird, S.M., and Wilson, D.B., Transfer of a functional human immune system to mice with severe combined immunodeficiency, Nature, 335 (6187), 256-259, 1988.

99. Mosier, D.E., Gulizia, R.J., Baird, S.M., Wilson, D.B., Spector, D.H., and Spector, S.A., Human immunodeficiency virus infection of human-PBL-SCID mice, Science, 251 (4995), 791-794, 1991.

100. Mosier, D.E., Gulizia, R.J., MacIsaac, 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 (5108), 689-692, 1993.

101. Poignard, P., Sabbe, R., Picchio, G.R., Wang, M., Gulizia, R.J., Katinger, H., Parren, P.W., Mosier, D.E., and Burton, D.R., Neutralizing antibodies have limited effects on the control of established HIV-1 infection in vivo, Immunity, 10 (4), 431-438, 1999.

102. Yoshida, A., Tanaka, R., Murakami, T., Takahashi, Y., Koyanagi, Y., Nakamura, M., Ito, M., Yamamoto,

N., and Tanaka, Y., Induction of protective immune responses against R5 human immunodeficiency virus type 1 (HIV-1) infection in hu-PBL-SCID mice by intrasplenic immunization with HIV-1-pulsed dendritic cells: possible involvement of a novel factor of human CD4(+) T-cell origin, J. Virol., 77 (16), 8719-8728, 2003.

103. Lapenta, C., Santini, S.M., Logozzi, M., Spada, M., Andreotti, M., Di Pucchio, T., Parlato, S., and Belardelli, F., Potent immune response against HIV-1 and protection from virus challenge in hu-PBL- SCID mice immunized with inactivated virus-pulsed dendritic cells generated in the presence of IFN-,

J. Exp. Med., 198 (2), 361-367, 2003.

104. Lapenta, C., Santini, S.M., Proietti, E., Rizza, P., Logozzi, M., Spada, M., Parlato, S., Fais, S., Pitha, P.M., and Belardelli, F., Type I interferon is a powerful inhibitor of in vivo HIV-1 infection and preserves human CD4(+) T cells from virus-induced depletion in SCID mice transplanted with human cells, Virology, 263 (1), 78-88, 1999.

105. Delhem, N., Hadida, F., Gorochov, G., Carpentier, F., de Cavel, J.P., Andreani, J.F., Autran, B., and Cesbron, J.Y., Primary Th1 cell immunization against HIVgp160 in SCID-hu mice coengrafted with peripheral blood lymphocytes and skin, J. Immunol., 161 (4), 2060-2069, 1998.

106. Boyle, M.J., Connors, M., Flanigan, M.E., Geiger, S.P., Ford, H., Jr., Baseler, M., Adelsberger, J., Davey, R.T., Jr., and Lane, H.C., The human HIV/peripheral blood lymphocyte (PBL)-SCID mouse. A modified human PBL-SCID model for the study of HIV pathogenesis and therapy, J. Immunol., 154 (12), 6612-6623, 1995.

107. Koup, R.A., Safrit, J.T., Weir, R., and Gauduin, M.C., Defining antibody protection against HIV-1 transmission in Hu-PBL-SCID mice, Semin. Immunol., 8 (4), 263-268, 1996.

108. Santini, S.M., Lapenta, C., Logozzi, M., Parlato, S., Spada, M., Di Pucchio, T., and Belardelli, F., Type I interferon as a powerful adjuvant for monocyte-derived dendritic cell development and activity in vitro and in Hu-PBL-SCID mice, J. Exp. Med., 191 (10), 1777-1788, 2000.

109. Picchio, G.R., Valdez, H., Sabbe, R., Landay, A.L., Kuritzkes, D.R., Lederman, M.M., and Mosier, D.E., Altered viral fitness of HIV-1 following failure of protease inhibitor-based therapy, J. Acquir. Immune Defic. Syndr., 25 (4), 289-295, 2000.

110. Vieillard, V., Jouveshomme, S., Leflour, N., Jean-Pierre, E., Debre, P., De Maeyer, E., and Autran, B., Transfer of human CD4(+) T lymphocytes producing interferon in Hu-PBL-SCID mice controls human immunodeficiency virus infection, J. Virol., 73 (12), 10281-10288, 1999.

111. Okamoto, Y., Eda, Y., Ogura, A., Shibata, S., Amagai, T., Katsura, Y., Asano, T., Kimachi, K., Makizumi, K., and Honda, M., In SCID-hu mice, passive transfer of a humanized antibody prevents infection and atrophic change of medulla in human thymic implant due to intravenous inoculation of primary HIV-1 isolate, J. Immunol., 160 (1), 69-76, 1998.

112. Gauduin, M.C., Parren, P.W., Weir, R., Barbas, C.F., Burton, D.R., and Koup, R.A., Passive immuni­zation with a human monoclonal antibody protects hu-PBL-SCID mice against challenge by primary isolates of HIV-1, Nat. Med., 3 (12), 1389-1393, 1997.

113. Reinhardt, B., Torbett, B.E., Gulizia, R.J., Reinhardt, P.P., Spector, S.A., and Mosier, D.E., Human immunodeficiency virus type 1 infection of neonatal severe combined immunodeficient mice xenografted with human cord blood cells, AIDS Res. Hum. Retroviruses, 10 (2), 131-141, 1994.

114. Mosier, D.E., Viral pathogenesis in hu-PBL-SCID mice, Semin. Immunol., 8 (4), 255-262, 1996.

115. Rizza, P., Santini, S.M., Logozzi, M.A., Lapenta, C., Sestili, P., Gherardi, G., Lande, R., Spada, M., Parlato, S., Belardelli, F., and Fais, S., T-cell dysfunctions in hu-PBL-SCID mice infected with human immunodeficiency virus (HIV) shortly after reconstitution: in vivo effects of HIV on highly activated human immune cells, J. Virol., 70 (11), 7958-7964, 1996.

116. 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 (9), 3509-3520, 1996.

117. Fais, S., Lapenta, C., Santini, S.M., Spada, M., Parlato, S., Logozzi, M., Rizza, P., and Belardelli, F., Human immunodeficiency virus type 1 strains R5 and X4 induce different pathogenic effects in hu- PBL-SCID mice, depending on the state of activation/differentiation of human target cells at the time of primary infection, J. Virol., 73 (8), 6453-6459, 1999.

118. Picchio, G.R., Gulizia, R.J., and Mosier, D.E., Chemokine receptor CCR5 genotype influences the kinetics of human immunodeficiency virus type 1 infection in human PBL-SCID mice, J. Virol., 71

(9), 7124-7127, 1997.

119. Gomez-Roman, V.R., Vazquez, J.A., del Carmen Basualdo, M., Estrada, F.J., Ramos-Kuri, M., and Soler, C., Nef/long terminal repeat quasispecies from HIV type 1-infected Mexican patients with different progression patterns and their pathogenesis in hu-PBL-SCID mice, AIDS Res. Hum. Retro­viruses, 16 (5), 441-452, 2000.

120. Gulizia, R.J., Collman, R.G., Levy, J.A., Trono, D., and Mosier, D.E., Deletion of Nef slows but does not prevent CD4-positive T-cell depletion in human immunodeficiency virus type 1-infected human- PBL-SCID mice, J. Virol., 71 (5), 4161-4164, 1997.

121. Kawano, Y., Tanaka, Y., Misawa, N., Tanaka, R., Kira, J.I., Kimura, T., Fukushi, M., Sano, K., Goto, T., Nakai, M., Kobayashi, T., Yamamoto, N., and Koyanagi, Y., Mutational analysis of human immu­nodeficiency virus type 1 (HIV-1) accessory genes: requirement of a site in the Nef gene for HIV-1 replication in activated CD4+ T cells in vitro and in vivo, J. Virol., 71 (11), 8456-8466, 1997.

122. Koyanagi, Y., Tanaka, Y., Kira, J., Ito, M., Hioki, K., Misawa, N., Kawano, Y., Yamasaki, K., Tanaka, R., Suzuki, Y., Ueyama, Y., Terada, E., Tanaka, T., Miyasaka, M., Kobayashi, T., Kumazawa, Y., and Yamamoto, N., Primary human immunodeficiency virus type 1 viremia and central nervous system invasion in a novel hu-PBL-immunodeficient mouse strain, J. Virol., 71 (3), 2417-2424, 1997.

123. Kataoka, S., Satoh, J., Fujiya, H., Toyota, T., Suzuki, R., Itoh, K., and Kumagai, K., Immunologic aspects of the nonobese diabetic (NOD) mouse. Abnormalities of cellular immunity, Diabetes, 32 (3), 247-253, 1983.

124. Koyanagi, Y., Tanaka, Y., Tanaka, R., Misawa, N., Kawano, Y., Tanaka, T., Miyasaka, M., Ito, M., Ueyama, Y., and Yamamoto, N., High levels of viremia in hu-PBL-NOD-scid mice with HIV-1 infection, Leukemia, 11 (Suppl. 3), 109-112, 1997.

125. Miura, Y., Misawa, N., Maeda, N., Inagaki, Y., Tanaka, Y., Ito, M., Kayagaki, N., Yamamoto, N., Yagita, H., Mizusawa, H., and Koyanagi, Y., Critical contribution of tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) to apoptosis of human CD4+ T cells in HIV-1-infected hu-PBL- NOD-SCID mice, J. Exp. Med., 193 (5), 651-660, 2001.

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

K., Mizusawa, H., and Koyanagi, Y., 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 (5), 2777-2782, 2003.

127. Chen, W., Sulcove, J., Frank, I., Jaffer, S., Ozdener, H., and Kolson, D.L., Development of a human neuronal cell model for human immunodeficiency virus (HIV)-infected macrophage-induced neurotox­icity: apoptosis induced by HIV type 1 primary isolates and evidence for involvement of the Bcl-2/ Bcl-xL-sensitive intrinsic apoptosis pathway, J. Virol., 76 (18), 9407-9419, 2002.

128. del Real, G., Llorente, M., Bosca, L., Hortelano, S., Serrano, A., Lucas, P., Gomez, L., Toran, J.L., Redondo, C., and Martinez, C., Suppression of HIV-1 infection in linomide-treated SCID-hu-PBL mice, AIDS, 12 (8), 865-872, 1998.

129. Maddon, PJ., Dalgleish, A.G., McDougal, J.S., Clapham, P.R., Weiss, R.A., and Axel, R., The T4 gene encodes the AIDS virus receptor and is expressed in the immune system and the brain, Cell, 47 (3), 333-348, 1986.

130. Lores, P., Boucher, V., Mackay, C., Pla, M., Von Boehmer, H., Jami, J., Barre-Sinoussi, F., and Weill, J.C., Expression of human CD4 in transgenic mice does not confer sensitivity to human immunode­ficiency virus infection, AIDS Res. Hum. Retroviruses, 8 (12), 2063-2071, 1992.

131. Mariani, R., Chen, D., Schrofelbauer, B., Navarro, F., Konig, R., Bollman, B., Munk, C., Nymark- McMahon, H., and Landau, N.R., Species-specific exclusion of APOBEC3G from HIV-1 virions by Vif, Cell, 114 (1), 21-31, 2003.

132. Mariani, R., Rasala, B.A., Rutter, G., Wiegers, K., Brandt, S.M., Krausslich, H.G., and Landau, N.R., Mouse-human heterokaryons support efficient human immunodeficiency virus type 1 assembly, J. Virol., 75 (7), 3141-3151, 2001.

133. Mariani, R., Rutter, G., Harris, M.E., Hope, T.J., Krausslich, H.G., and Landau, N.R., A block to human immunodeficiency virus type 1 assembly in murine cells, J. Virol., 74 (8), 3859-3870,

2000.

134. Hatziioannou, T., Cowan, S., Von Schwedler, U.K., Sundquist, W.I., and Bieniasz, P.D., Species­specific tropism determinants in the human immunodeficiency virus type 1 capsid, J. Virol., 78 (11), 6005-6012, 2004.

135. Bieniasz, P.D., Grdina, T.A., Bogerd, H.P., and Cullen, B.R., Recruitment of a protein complex containing Tat and cyclin T1 to TAR governs the species specificity of HIV-1 Tat, EMBO J., 17 (23), 7056-7065, 1998.

136. Bieniasz, P.D. and Cullen, B.R., Multiple blocks to human immunodeficiency virus type 1 replication in rodent cells, J. Virol., 74 (21), 9868-9877, 2000.

137. Zimmerman, C., Klein, K.C., Kiser, P.K., Singh, A.R., Firestein, B.L., Riba, S.C., and Lingappa, J.R., Identification of a host protein essential for assembly of immature HIV-1 capsids, Nature, 415 (6867), 88-92, 2002.

138. Garber, M.E., Wei, P., KewalRamani, V.N., Mayall, T.P., Herrmann, C.H., Rice, A.P., Littman, D.R., and Jones, K.A., The interaction between HIV-1 Tat and human cyclin T1 requires zinc and a critical cysteine residue that is not conserved in the murine CycT1 protein, Genes Dev., 12 (22), 3512-3527, 1998.

139. Dragic, T., Litwin, V., Allaway, G.P., Martin, S.R., Huang, Y., Nagashima, K.A., Cayanan, C., Maddon, PJ., Koup, R.A., Moore, J.P., and Paxton, W.A., HIV-1 entry into CD4+ cells is mediated by the chemokine receptor CC-CKR-5, Nature, 381 (6584), 667-673, 1996.

140. Choe, H., Farzan, M., Sun, Y., Sullivan, N., Rollins, B., Ponath, P.D., Wu, L., Mackay, C.R., LaRosa,

G., Newman, W., Gerard, N., Gerard, C., and Sodroski, J., The -chemokine receptors CCR3 and CCR5 facilitate infection by primary HIV-1 isolates, Cell, 85 (7), 1135-1148, 1996.

141. Deng, H., Liu, R., Ellmeier, W., Choe, S., Unutmaz, D., Burkhart, M., Di Marzio, P., Marmon, S., Sutton, R.E., Hill, C.M., Davis, C.B., Peiper, S.C., Schall, T.J., Littman, D.R., and Landau, N.R., Identification of a major co-receptor for primary isolates of HIV-1, Nature, 381 (6584), 661-666,

1996.

142. Feng, Y., Broder, C.C., Kennedy, P.E., and Berger, E.A., HIV-1 entry cofactor: functional cDNA cloning of a seven-transmembrane, G protein-coupled receptor, Science, 272 (5263), 872-877, 1996.

143. Browning, J., Horner, J.W., Pettoello-Mantovani, M., Raker, C., Yurasov, S., DePinho, R.A., and Goldstein, H., Mice transgenic for human CD4 and CCR5 are susceptible to HIV infection, Proc. Natl. Acad. Sci. U.S.A., 94 (26), 14637-14641, 1997.

144. Sawada, S., Gowrishankar, K., Kitamura, R., Suzuki, M., Suzuki, G., Tahara, S., and Koito, A., Disturbed CD4+ T cell homeostasis and in vitro HIV-1 susceptibility in transgenic mice expressing T cell line-tropic HIV-1 receptors, J. Exp. Med., 187 (9), 1439-1449, 1998.

145. Keppler, O.T., Yonemoto, W., Welte, F.J., Patton, K.S., Iacovides, D., Atchison, R.E., Ngo, T., Hirschberg, D.L., Speck, R.F., and Goldsmith, M.A., Susceptibility of rat-derived cells to replication by human immunodeficiency virus type 1, J. Virol., 75 (17), 8063-8073, 2001.

146. Keppler, O.T., Welte, F.J., Ngo, T.A., Chin, P.S., Patton, K.S., Tsou, C.L., Abbey, N.W., Sharkey, M.E., Grant, R.M., You, Y., Scarborough, J.D., Ellmeier, W., Littman, D.R., Stevenson, M., Charo,

I. F., Herndier, B.G., Speck, R.F., and Goldsmith, M.A., Progress toward a human CD4/CCR5 trans­genic rat model for de novo infection by human immunodeficiency virus type 1, J. Exp. Med., 195 (6), 719-736, 2002.

147. Leonard, J.M., Abramczuk, J.W., Pezen, D.S., Rutledge, R., Belcher, J.H., Hakim, F., Shearer, G., Lamperth, L., Travis, W., Fredrickson, T., Notkins, A.L., and Martin, M.A., Development of disease and virus recovery in transgenic mice containing HIV proviral DNA, Science, 242 (4886), 1665-1670, 1988.

148. Hanna, Z., Kay, D.G., Cool, M., Jothy, S., Rebai, N., and Jolicoeur, P., Transgenic mice expressing human immunodeficiency virus type 1 in immune cells develop a severe AIDS-like disease, J. Virol., 72 (1), 121-132, 1998.

149. Dickie, P., Gazzinelli, R., and Chang, L.J., Models of HIV type 1 proviral gene expression in wild­type HIV and MLV/HIV transgenic mice, AIDS Res. Hum. Retroviruses, 12 (12), 1103-1116, 1996.

150. Wang, E.J., Pettoello-Mantovani, M., Anderson, C.M., Osiecki, K., Moskowitz, D., and Goldstein,

H., Development of a novel transgenic mouse/SCID-hu mouse system to characterize the in vivo behavior of reservoirs of human immunodeficiency virus type 1-infected cells, J. Infect. Dis., 186

(10), 1412-1421, 2002.

151. Wang, E.J., Sun, J., Pettoello-Mantovani, M., Anderson, C.M., Osiecki, K., Zhao, M.L., Lopez, L., Lee, S.C., Berman, J.W., and Goldstein, H., Microglia from mice transgenic for a provirus encoding a monocyte-tropic HIV type 1 isolate produce infectious virus and display in vitro and in vivo upregulation of lipopolysaccharide-induced chemokine gene expression, AIDS Res. Hum. Retrovi­ruses, 19 (9), 755-765, 2003.

152. Browning Paul, J., Wang, E.J., Pettoello-Mantovani, M., Raker, C., Yurasov, S., Goldstein, M.M., Horner, J.W., Chan, J., and Goldstein, H., Mice transgenic for monocyte-tropic HIV type 1 produce infectious virus and display plasma viremia: a new in vivo system for studying the postintegration phase of HIV replication, AIDS Res. Hum. Retroviruses, 16 (5), 481-492, 2000.

153. Poudrier, J., Weng, X., Kay, D.G., Pare, G., Calvo, E.L., Hanna, Z., Kosco-Vilbois, M.H., and Jolicoeur, P., The AIDS disease of CD4C/HIV transgenic mice shows impaired germinal centers and autoanti­bodies and develops in the absence of IFN- and IL-6, Immunity, 15 (2), 173-185, 2001.

154. Rosenberg, Y.J., Lewis, M.G., Greenhouse, J.J., Cafaro, A., Leon, E.C., Brown, C.R., Bieg, K.E., and Kosco-Vilbois, M.H., Enhanced follicular dendritic cell function in lymph nodes of simian immuno­deficiency virus-infected macaques: consequences for pathogenesis, Eur. J. Immunol., 27 (12), 3214-3222, 1997.

155. De, S.K., Devadas, K., and Notkins, A.L., Elevated levels of tumor necrosis factor (TNF-) in human immunodeficiency virus type 1-transgenic mice: prevention of death by antibody to TNF-, J. Virol., 76 (22), 11710-11714, 2002.

156. De, S.K., Wohlenberg, C.R., Marinos, N.J., Doodnauth, D., Bryant, J.L., and Notkins, A.L., Human chorionic gonadotropin hormone prevents wasting syndrome and death in HIV-1 transgenic mice,

J. Clin. Invest., 99 (7), 1484-1491, 1997.

157. Santoro, T.J., Bryant, J.L., Pellicoro, J., Klotman, M.E., Kopp, J.B., Bruggeman, L.A., Franks, R.R., Notkins, A.L., and Klotman, P.E., Growth failure and AIDS-like cachexia syndrome in HIV-1 trans­genic mice, Virology, 201 (1), 147-151, 1994.

158. Tinkle, B.T., Ueda, H., Ngo, L., Luciw, P.A., Shaw, K., Rosen, C.A., and Jay, G., Transgenic dissection of HIV genes involved in lymphoid depletion, J. Clin. Invest., 100 (1), 32-39, 1997.

159. Hanna, Z., Kay, D.G., Rebai, N., Guimond, A., Jothy, S., and Jolicoeur, P., Nef harbors a major determinant of pathogenicity for an AIDS-like disease induced by HIV-1 in transgenic mice, Cell, 95 (2), 163-175, 1998.

160. Hanna, Z., Priceputu, E., Kay, D.G., Poudrier, J., Chrobak, P., and Jolicoeur, P., In vivo mutational analysis of the N-terminal region of HIV-1 Nef reveals critical motifs for the development of an AIDS­like disease in CD4C/HIV transgenic mice, Virology, 327 (2), 273-286, 2004.

161. Hanna, Z., Weng, X., Kay, D.G., Poudrier, J., Lowell, C., and Jolicoeur, P., The pathogenicity of human immunodeficiency virus (HIV) type 1 Nef in CD4C/HIV transgenic mice is abolished by mutation of its SH3-binding domain, and disease development is delayed in the absence of Hck, J. Virol., 75 (19), 9378-9392, 2001.

162. Weng, X., Priceputu, E., Chrobak, P., Poudrier, J., Kay, D.G., Hanna, Z., Mak, T.W., and Jolicoeur, P., CD4+ T cells from CD4C∕HIVNef transgenic mice show enhanced activation in vivo with impaired proliferation in vitro but are dispensable for the development of a severe AIDS-like organ disease, J. Virol., 78 (10), 5244-5257, 2004.

163. Lindemann, D., Wilhelm, R., Renard, P., Althage, A., Zinkernagel, R., and Mous, J., Severe immuno­deficiency associated with a human immunodeficiency virus 1 NEF/3-long terminal repeat transgene, J. Exp. Med., 179 (3), 797-807, 1994.

164. Skowronski, J., Parks, D., and Mariani, R., Altered T cell activation and development in transgenic mice expressing the HIV-1 Nef gene, EMBO J., 12 (2), 703-713, 1993.

165. Simard, M.C., Chrobak, P., Kay, D.G., Hanna, Z., Jothy, S., and Jolicoeur, P., Expression of simian immunodeficiency virus Nef in immune cells of transgenic mice leads to a severe AIDS-like disease, J. Virol., 76 (8), 3981-3995, 2002.

166. Kim, B.O., Liu, Y., Ruan, Y., Xu, Z.C., Schantz, L., and He, J.J., Neuropathologies in transgenic mice expressing human immunodeficiency virus type 1 Tat protein under the regulation of the astrocyte­specific glial fibrillary acidic protein promoter and doxycycline, Am. J. Pathol., 162 (5), 1693-1707, 2003.

167. Yasuda, J., Miyao, T., Kamata, M., Aida, Y., and Iwakura, Y., T cell apoptosis causes peripheral T cell depletion in mice transgenic for the HIV-1 Vpr gene, Virology, 285 (2), 181-192, 2001.

168. Adle-Biassette, H., Levy, Y., Colombel, M., Poron, F., Natchev, S., Keohane, C., and Gray, F., Neuronal apoptosis in HIV infection in adults, Neuropathol. Appl. Neurobiol., 21 (3), 218-227, 1995.

169. Hesselgesser, J., Taub, D., Baskar, P., Greenberg, M., Hoxie, J., Kolson, D.L., and Horuk, R., Neuronal apoptosis induced by HIV-1 gp120 and the chemokine SDF-1 is mediated by the chemokine receptor CXCR4, Curr. Biol., 8 (10), 595-598, 1998.

170. Meucci, O., Fatatis, A., Simen, A.A., Bushell, T.J., Gray, P.W., and Miller, R.J., Chemokines regulate hippocampal neuronal signaling and gp120 neurotoxicity, Proc. Natl. Acad. Sci. U.S.A., 95 (24), 14500-14505, 1998.

171. Garden, G.A., Budd, S.L., Tsai, E., Hanson, L., Kaul, M., D’Emilia, D.M., Friedlander, R.M., Yuan, J., Masliah, E., and Lipton, S.A., Caspase cascades in human immunodeficiency virus-associated neurodegeneration, J. Neurosci., 22 (10), 4015-4024, 2002.

172. Alter, H.J., Eichberg, J.W., Masur, H., Saxinger, W.C., Gallo, R., Macher, A.M., Lane, H.C., and Fauci, A.S., Transmission of HTLV-III infection from human plasma to chimpanzees: an animal model for AIDS, Science, 226 (4674), 549-552, 1984.

173. Francis, D.P., Feorino, P.M., Broderson, J.R., McClure, H.M., Getchell, J.P., McGrath, C.R., Swenson, B., McDougal, J.S., Palmer, E.L., Harrison, A.K., Barresinoussi, F., Chermann, J.C., Montagnier, L., Curran, J.W., Cabradilla, C.D., and Kalyanaraman, V.S., Infection of chimpanzees with lymphad­enopathy-associated virus, Lancet, 2 (8414), 1276-1277, 1984.

174. Ghosh, S.K., Fultz, P.N., Keddie, E., Saag, M.S., Sharp, P.M., Hahn, B.H., and Shaw, G.M., A molecular clone of HIV-1 tropic and cytopathic for human and chimpanzee lymphocytes, Virology, 194 (2), 858-864, 1993.

175. Shibata, R., Hoggan, M.D., Broscius, C., Englund, G., Theodore, T.S., Buckler-White, A., Arthur,

L. O., Israel, Z., Schultz, A., Lane, H.C., and Martin, M.A., Isolation and characterization of a syncytium-inducing, macrophage/T-cell line-tropic human immunodeficiency virus type 1 isolate that readily infects chimpanzee cells in vitro and in vivo, J. Virol., 69 (7), 4453-4462, 1995.

176. Ondoa, P., Davis, D., Kestens, L., Vereecken, C., Garcia Ribas, S., Fransen, K., Heeney, J., and van der Groen, G., In vitro susceptibility to infection with SIVcpz and HIV-1 is lower in chimpanzee than in human peripheral blood mononuclear cells, J. Med. Virol., 67 (3), 301-311, 2002.

177. Fultz, P.N., Srinivasan, A., Greene, C.R., Butler, D., Swenson, R.B., and McClure, H.M., Superinfec­tion of a chimpanzee with a second strain of human immunodeficiency virus, J. Virol., 61 (12), 4026-4029, 1987.

178. Novembre, F.J., Saucier, M., Anderson, D.C., Klumpp, S.A., O'Neil, S.P., Brown, C.R., II, Hart, C.E., Guenthner, P.C., Swenson, R.B., and McClure, H.M., Development of AIDS in a chimpanzee infected with human immunodeficiency virus type 1, J. Virol., 71 (5), 4086-4091, 1997.

179. Mwaengo, D.M. and Novembre, F.J., Molecular cloning and characterization of viruses isolated from chimpanzees with pathogenic human immunodeficiency virus type 1 infections, J. Virol., 72 (11), 8976-8987, 1998.

180. Novembre, F.J., de Rosayro, J., Nidtha, S., O'Neil, S.P., Gibson, T.R., Evans-Strickfaden, T., Hart, C.E., and McClure, H.M., Rapid CD4(+) T-cell loss induced by human immunodeficiency virus type 1(NC) in uninfected and previously infected chimpanzees, J. Virol., 75 (3), 1533-1539,

2001.

181. O'Neil, S.P., Novembre, F.J., Hill, A.B., Suwyn, C., Hart, C.E., Evans-Strickfaden, T., Anderson, D.C., deRosayro, J., Herndon, J.G., Saucier, M., and McClure, H.M., Progressive infection in a subset of HIV-1-positive chimpanzees, J. Infect. Dis., 182 (4), 1051-1062, 2000.

182. 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.

183. Prince, A.M., Chimpanzee pathogenic strains of HIV type 1 (Letter), AIDS Res. Hum. Retroviruses, 13 (15), 1259, 1997.

184. Prince, A.M., Allan, J., Andrus, L., Brotman, B., Eichber, J., Fouts, R., Goodall, J., Marx, P., Murthy, K.K., McGreal, S., and Noon, C., Virulent HIV strains, chimpanzees, and trial vaccines, Science, 283 (5405), 1117-1118, 1999.

185. 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 (6), 2964-2976, 1997.

186. Gougeon, M.L., Garcia, S., Heeney, J., Tschopp, R., Lecoeur, H., Guetard, D., Rame, V., Dauguet, C., and Montagnier, L., Programmed cell death in AIDS-related HIV and SIV infections, AIDS Res. Hum. Retroviruses, 9 (6), 553-563, 1993.

187. Schuitemaker, H., Meyaard, L., Kootstra, 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 (5), 1140-1147, 1993.

188. Ehret, A., Westendorp, M.O., Herr, I., Debatin, K.M., Heeney, J.L., Frank, R., and Krammer, P.H., Resistance of chimpanzee T cells to human immunodeficiency virus type 1 Tat-enhanced oxidative stress and apoptosis, J. Virol., 70 (9), 6502-6507, 1996.

189. Estaquier, J., Idziorek, T., de Bels, F., Barre-Sinoussi, F., Hurtrel, B., Aubertin, A.M., Venet, A., Mehtali, M., Muchmore, E., Michel, P., Mouton, Y., Girard, M., and Ameisen, J.C., 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.

190. Shibata, R., Sakai, H., Kiyomasu, T., Ishimoto, A., Hayami, M., and Adachi, A., Generation and characterization of infectious chimeric clones between human immunodeficiency virus type 1 and simian immunodeficiency virus from an African green monkey, J. Virol., 64 (12), 5861-5868, 1990.

191. Shibata, R., Kawamura, M., Sakai, H., Hayami, M., Ishimoto, A., and Adachi, A., Generation of a chimeric human and simian immunodeficiency virus infectious to monkey peripheral blood mononu­clear cells, J. Virol., 65 (7), 3514-3520, 1991.

192. Joag, S.V., Li, Z., Foresman, L., Stephens, E.B., Zhao, L.J., Adany, I., Pinson, D.M., McClure, H.M., and Narayan, O., Chimeric simian/human immunodeficiency virus that causes progressive loss of CD4+ T cells and AIDS in pig-tailed macaques, J. Virol., 70 (5), 3189-3197, 1996.

193. Shibata, R., Maldarelli, F., Siemon, C., Matano, T., Parta, M., Miller, G., Fredrickson, T., and Martin,

M. A., Infection and pathogenicity of chimeric simian-human immunodeficiency viruses in macaques: determinants of high virus loads and CD4 cell killing, J. Infect. Dis., 176 (2), 362-373, 1997.

194. Reimann, K.A., Li, J.T., Veazey, R., Halloran, M., Park, I.W., Karlsson, G.B., Sodroski, J., and Letvin,

N. L., A chimeric simian/human immunodeficiency virus expressing a primary patient human immu­nodeficiency virus type 1 isolate Env causes an AIDS-like disease after in vivo passage in rhesus monkeys, J. Virol., 70 (10), 6922-6928, 1996.

195. Reinberger, S., Spring, M., Nisslein, T., Stahl-Hennig, C., Hunsmann, G., and Dittmer, U., Kinetics of lymphocyte apoptosis in macaques infected with different simian immunodeficiency viruses or simian/human immunodeficiency hybrid viruses, Clin. Immunol., 90 (1), 141-146, 1999.

196. Iida, T., Kita, M., Kuwata, T., Miura, T., Ibuki, K., Ui, M., Hayami, M., and Imanishi, J., Apoptosis induced by in vitro infection with simian-human immunodeficiency chimeric virus in macaque and human peripheral blood mononuclear cells, AIDS Res. Hum. Retroviruses, 17 (15), 1387-1393, 2001.

197. Iida, T., Ichimura, H., Shimada, T., Ibuki, K., Ui, M., Tamaru, K., Kuwata, T., Yonehara, S., Imanishi, J., and Hayami, M., Role of apoptosis induction in both peripheral lymph nodes and thymus in progressive loss of CD4+ cells in SHIV-infected macaques, AIDS Res. Hum. Retroviruses, 16 (1), 9-18, 2000.

198. Yoshino, N., Ryu, T., Sugamata, M., Ihara, T., Ami, Y., Shinohara, K., Tashiro, F., and Honda, M., Direct detection of apoptotic cells in peripheral blood from highly pathogenic SHIV-inoculated monkey, Biochem. Biophys. Res. Commun., 268 (3), 868-874, 2000.

199. Sasaki, Y., Ami, Y., Nakasone, T., Shinohara, K., Takahashi, E., Ando, S., Someya, K., Suzaki, Y., and Honda, M., Induction of CD95 ligand expression on T lymphocytes and B lymphocytes and its contribution to apoptosis of CD95-up-regulated CD4+ T lymphocytes in macaques by infection with a pathogenic simian/human immunodeficiency virus, Clin. Exp. Immunol., 122 (3), 381-389, 2000.

200. Igarashi, T., Brown, C.R., Byrum, R.A., Nishimura, Y., Endo, Y., Plishka, R.J., Buckler, C., Buckler­White, A., Miller, G., Hirsch, V.M., and Martin, M.A., Rapid and irreversible CD4+ T-cell depletion induced by the highly pathogenic simian/human immunodeficiency virus SHIV(DH12R) is systemic and synchronous, J. Virol., 76 (1), 379-391, 2002.

201. Wallace, M., Waterman, P.M., Mitchen, J.L., Djavani, M., Brown, C., Trivedi, P., Horejsh, D., Dykhuizen, M., Kitabwalla, M., and Pauza, C.D., Lymphocyte activation during acute simian/human immunodeficiency virus SHIV(89.6PD) infection in macaques, J. Virol., 73 (12), 10236-10244, 1999.

202. 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 (4), 581-585, 1996.

203. Badley, A.D., Pilon, A.A., Landay, A., and Lynch, D.H., Mechanisms of HIV-associated lymphocyte apoptosis, Blood, 96 (9), 2951-2964, 2000.

204. Bahner, I., Kearns, K., Hao, Q.L., Smogorzewska, E.M., and Kohn, D.B., Transduction of human CD34+ hematopoietic progenitor cells by a retroviral vector expressing an RRE decoy inhibits human immunodeficiency virus type 1 replication in myelomonocytic cells produced in long-term culture, J. Virol., 70 (7), 4352-4360, 1996.

205. Bonyhadi, M.L., Moss, K., Voytovich, A., Auten, J., Kalfoglou, C., Plavec, I., Forestell, S., Su, L., Bohnlein, E., and Kaneshima, H., RevM10-expressing T cells derived in vivo from transduced human hematopoietic stem-progenitor cells inhibit human immunodeficiency virus replication, J. Virol., 71 (6), 4707-4716, 1997.

206. Bauer, G., Valdez, P., Kearns, K., Bahner, I., Wen, S.F., Zaia, J.A., and Kohn, D.B., Inhibition of human immunodeficiency virus-1 (HIV-1) replication after transduction of granulocyte colony-stim­ulating factor-mobilized CD34+ cells from HIV-1-infected donors using retroviral vectors containing anti-HIV-1 genes, Blood, 89 (7), 2259-2267, 1997.

207. Gervaix, A., Schwarz, L., Law, P., Ho, A.D., Looney, D., Lane, T., and Wong-Staal, F., Gene therapy targeting peripheral blood CD34+ hematopoietic stem cells of HIV-infected individuals, Hum. Gene Ther., 8 (18), 2229-2238, 1997.

208. Su, L., Lee, R., Bonyhadi, M., Matsuzaki, H., Forestell, S., Escaich, S., Bohnlein, E., and Kaneshima, H., Hematopoietic stem cell-based gene therapy for acquired immunodeficiency syndrome: efficient transduction and expression of RevM10 in myeloid cells in vivo and in vitro, Blood, 89 (7), 2283-2290,

1997.

209. Yu, M., Leavitt, M.C., Maruyama, M., Yamada, O., Young, D., Ho, A.D., and Wong-Staal, F., Intra­cellular immunization of human fetal cord blood stem/progenitor cells with a ribozyme against human immunodeficiency virus type 1, Proc. Natl. Acad. Sci. U.S.A., 92 (3), 699-703, 1995.

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Source: Badley A.D. (ed.). Cell Death During HIV Infection. Taylor & Francis,2006. — 511 p.. 2006
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