Springer Nature is making Coronavirus research free. View research | View latest news | Sign up for updates

Regulation of cellular gene expression and function by the human immunodeficiency virus type 1 tat protein


The human immunodeficiency virus type 1 Tat protein is a potent activator of viral gene expression and replication. Tat can also affect the expression of cellular genes including cytokines, extracellular matrix proteins, enzymes degrading the basement membrane and cell cycle-related proteins, and can regulate cellular functions such as growth, migration and angiogenesis. In addition, under certain circumstances, Tat may have tumorigenic effects. These activities of Tat appear to be mediated by different mechanisms such as the transactivation of cellular gene expression or the interaction of extracellular Tat with the cell membrane through both receptor-mediated and nonreceptor-mediated interactions. Deregulation of cellular gene expression and function by Tat cause abnormalities which may participate in AIDS pathogenesis and in the development of AIDS-associated disorders.

This is a preview of subscription content, log in to check access.


  1. 1

    Albini A, Barillari G, Benelli R, Gallo RC, Ensoli B. Tat, the human immunodeficiency virus type 1 regulatory protein has angiogenic properties. Proc Natl Acad Sci USA, in press.

  2. 2

    Albini A, Fontanini G, Masiello L, Tacchetti C, Bigini D, Luzzi P, Noonan DM, Stetler-Stevenson WG. Angiogenic potential in vivo by Kaposi's sarcoma cell-free supernatants and HIV-1tat product: inhibition of KS-like lesions by tissue inhibitor of metalloproteinase-2. AIDS 8:1237–1244;1994.

  3. 3

    Allen JB, Wong HL, Guyre PM, Simon GL, Wahl SM. Association of circulating receptor FcrRIII-positive monocytes in AIDS patients with elevated levels of transforming growth factor-β. J Clin Invest 87:1773–1779;1991.

  4. 4

    Arya SK, Guo C, Josephs SF, Wong-Staal F. Trans-activator gene of human T-lymphotropic virus type III (HTLV-III). Science 229:69–73;1985.

  5. 5

    Barillari G, Buonaguro L, Fiorelli V, Hoffman J, Michaels F, Gallo RC, Ensoli B. Effects of cytokines from activated immune cells on vascular cell growth and HIV-1 gene expression: implications for AIDS-Kaposi's sarcoma pathogenesis. J Immunol 149:3727–3734;1992.

  6. 6

    Barillari G, Gendelman R, Gallo RC, Ensoli B. The Tat protein of human immunodeficiency virus type 1, a growth factor for AIDS Kaposi sarcoma and cytokine-activated vascular cells, induces adhesion of the same cell types by using integrin receptors recognizing the RGD sequence. Proc Natl Acad Sci USA 90:7941–7945;1993.

  7. 7

    Barré-Sinoussi F, Chermann JC, Rey F, Nugeyre MT, Charmaret S, Gruest J, Dauget C, Axler-Blin C, Vezinet-Brun F, Rouzioux C, Rozenbaum W, Montagnier L. Isolation of a T-lymphotropic retrovirus from a patient at risk for acquired immunodeficiency syndrome. Science 220:868–871;1983.

  8. 8

    Benjouad A, Mabrouk K, Moulard M, Gluckman J-C, Rochat H, Rietschoten JV, Sabatier JM. Cytotoxic effect on lymphocytes of Tat from human immunodeficiency virus (HIV-1). FEBS J 319:119–124;1993.

  9. 9

    Berkhout B, Jeang KT. Tat transactivates the human immunodeficiency virus through a nascent RNA target. Cell 59:273–282;1989.

  10. 10

    Berkhout B, Gatignol A, Rabson AB, Jeang KT. TAR-independent activation of the HIV-1 LTR: evidence that Tat requires specific regions of the promoter. Cell 62:757–767;1990.

  11. 11

    Brake DA, Debouck C, Biesecker G. Identification of an Arg-Gly-Asp (RGD) cell adhesion site in human immunodeficiency virus type 1 transactivation protein, Tat. J Cell Biol 111:1275–1281;1990.

  12. 12

    Breen EC, Rezai AR, Nakajima K, Beall GN, Mitsuyasu RT, Hirano T, Kishimoto T, Martinez-Maza O. Infection with HIV is associated with elevated IL-6 levels and production. J Immunol 144:480–484;1990.

  13. 13

    Buonaguro L, Barillari G, Chang HK, Bohan CA, Kao V, Morgan R, Gallo RC, Ensoli B. Effects of the human immunodeficiency virus type 1 Tat protein on the expression of inflammatory cytokines. J Virol 66:7159–7167;1992.

  14. 14

    Buonaguro L, Buonaguro FM, Giraldo G, Ensoli B. The human immunodeficiency virus type 1 Tat protein transactivates tumor necrosis factor beta gene expression through a TAR-like structure. J Virol 68:2677–2682;1994.

  15. 15

    Caputo A, Sodroski JG, Haseltine WA. Constitutive expression of HIV-1 Tat protein in human Jurkat T cells using a BK virus vector. J Acquir Immune Defic Syndr 3:372–379;1990.

  16. 16

    Coffey RJ Jr, Derynck R, Wilcox JN, Bringman TS, Goustin AS, Moses HL, Pittelkow MR. Production and autoinduction of transforming growth factor-α in human keratinocytes. Nature (London) 328:817–820;1987.

  17. 17

    Crawford D, Zbinden I, Amstad P, Cerutti P. Oxidant stress induces the proto-oncogenes c-fos and c-myc in mouse epidermal cells. Oncogene 3:27–32;1988.

  18. 18

    Cupp C, Taylor JP, Khalili K, Amini S. Evidence for stimulation of the transforming growth factor β1 promoter by HIV-1 Tat in cells derived from CNS. Oncogene 8:2231–2236;1993.

  19. 19

    Dayton AI, Sodroski JG, Rosen CA, Goh WC, Haseltine WA. The trans-activator gene of the human T-cell lymphotrophic virus type III is required for replication. Cell 44:941–947;1986.

  20. 20

    Derynck R. The physiology of transforming growth factor-α. Adv Cancer Res 58:27–52;1992.

  21. 21

    Devary Y, Gottlieb RA, Lau LF, Karin M. Rapid and preferential activation of the c-jun gene during the mammalian UV response. Mol Cell Biol 11:2804–2811;1991.

  22. 22

    Edery I, Petryshyn R, Sonenberg N. Activation of double stranded RNA-dependent kinase (dsI) by the TAR region of HIV-1 mRNA: a novel translational control mechanism. Cell 56:303–312;1989.

  23. 23

    Ensoli B, Barillari G, Salahuddin SZ, Gallo RC, Wong-Staal F. Tat protein of HIV-1 stimulates growth of cells derived from Kaposi's sarcoma lesions of AIDS patients. Nature (London) 345:84–86;1990.

  24. 24

    Ensoli B, Barillari G, Gallo RC. Pathogenesis of AIDS associated KS. Hematol Oncol Clin North Am 5:281–295;1991.

  25. 25

    Ensoli B, Buonaguro L, Barillari G, Fiorelli V, Gendelman R, Morgan RA, Wingfield P, Gallo RC. Release, uptake, and effects of extracellular human immunodeficiency virus type 1 Tat protein on cell growth and viral transactivation. J Virol 67:277–287;1993.

  26. 26

    Ensoli B, Gendelman R, Markham P, Fiorelli V, Colombini S, Raffeld M, Cafaro A, Chang HK, Brady JN, Gallo RC. Synergy between basic fibroblast growth factor and HIV-1 Tat protein in induction of Kaposi's sarcoma. Nature (London) 371:674–680;1994.

  27. 27

    Fan J, Bass HZ, Fahey JL. Elevated IFN-gamma and decreased IL-2 gene expression are associated with HIV-1 infection. J Immunol 152:5031–5037;1993.

  28. 28

    Feinberg MB, Baltimore D, Frankel AD. The role of Tat in the human immunodeficiency virus life cycle indicates a primary effect on transcriptional elongation. Proc Natl Acad Sci USA 88:4045–4049;1991.

  29. 29

    Feng S, Holland EC. HIV-1 tat trans-activation requires the loop sequence within the TAR. Nature 334:165–167;1988.

  30. 30

    Fisher AG, Feinberg MB, Josephs SF, Harper ME, Marselle G, Reyes MA, Gonda MA, Aldovini A, Debouk C, Gallo RC, Wong-Staal F. The trans-activator gene of HTLV-III is essential for virus replication. Nature (London) 320:367–371;1986.

  31. 31

    Flores SC, Marecki JC, Harper KP, Bose SK, Nelson SK, McCord JM. Tat protein of human immunodeficiency virus type 1 represses expression of manganese superoxide dismutase in HeLa cells. Proc Natl Acad Sci USA 90:7632–7636;1993.

  32. 32

    Folks TM, Justement J, Kinter A, Dinarello CA, Fauci AS. Cytokine-induced expression of HIV-1 in a chronically infected promonocytic cell line. Science 238:800–802;1987.

  33. 33

    Folks TM, Clouse KA, Justement J, Rabson A, Duh E, Kehrl JH, Fauci AS. Tumor necrosis factor α induces expression of human immunodeficiency virus in a chronically infected T-cell clone. Proc Natl Acad Sci USA 86:2365–2368;1989.

  34. 34

    Frankel AD, Bredt D, Pabo C. Tat protein from immunodeficiency virus forms a metal-linked dimer. Science 240:70–73;1988.

  35. 35

    Frankel AD, Pabo CO. Cellular uptake of the Tat protein from human immunodeficiency virus. Cell 55:1189–1193;1988.

  36. 36

    Gallo RC, Salahuddin SZ, Popovic M, Shearer GM, Kaplan M, Haynes BF, Palker TJ, Redfield R, Oleske J, Safai B, White G, Foster P, Markham P. Frequent detection and isolation of cytopathic retroviruses (HTLV-III) from patients with AIDS and at risk for AIDS. Science 224:500–503;1984.

  37. 37

    Garcia JA, Harrich D, Soultanakis E, Wu F, Mitsuyasu R, Gaynor RB. Human immunodeficiency virus type 1 LTR TATA and TAR region sequences required for transcriptional regulation. EMBO J 8:765–778;1989.

  38. 38

    Gatignol A, Kumar A, Rabson A, Jeang KT. Identification of cellular proteins that bind to the human immunodeficiency virus type 1 trans-activation-responsive TAR element RNA. Proc Natl Acad Sci USA 86:7828–7832;1989.

  39. 39

    Gaya A, da la Calle O, Yague J, Alsinet E, Fernandez MD, Romero M, Faregat V, Martorell J, Vives J. IL-4 inhibits synthesis and IL-2-induced up-regulation of IL-2Rα but not IL-2β chain in CD4+ human T cells. J Immunol 146:4209–4214;1991.

  40. 40

    Gaynor R, Soultanakis E, Kuwabara M, Garcia J, Sigman DS. Specific binding of HeLa cell nuclear protein to RNA sequences in the human immunodeficiency virus transactivating region. Proc Natl Acad Sci USA 86:4858–4862;1989.

  41. 41

    Gentz R, Chen CH, Rosen CA. Bioassay for trans-activation using purified human immunodeficiency virustat-encoded protein: transactivation requires mRNA synthesis. Proc Natl Acad Sci USA 86:821–824;1989.

  42. 42

    Gerlach H, Lieberman H, Bach R, Godman G, Brett J, Stern D. Enhanced responsiveness of endothelium in the growing/motile state to tumor necrosis factor/cachetin. J Exp Med 170:913–931;1989.

  43. 43

    Goey H, Keller JR, Back T, Longo DL, Ruscetti FW, Wiltrout RH. Inhibition of early murine hemopoietic progenitor cell proliferation after in vivo locoregional administration of transforming growth factor-β 1. J Immunol 143:877–880;1989.

  44. 44

    Guerne PA, Sublet A, Lotz M. Growth factor responsiveness of human articular chondrocytes: distinct profiles in primary chondrocytes, sucultured chondrocytes and fibroblasts. J Cell Physiol 158:476–484;1994.

  45. 45

    Harrich D, Garcia J, Mitsuyasu R, Gaynor R. TAR independent activation of the human immunodeficiency virus in phorbol ester stimulated T lymphocytes. EMBO J 9:4417–4423;1990.

  46. 46

    Haseltine WA. Molecular biology of the human immunodeficiency virus type 1. FASEB J 5:2349–2360;1991.

  47. 47

    Hauber J, Cullen BR. Mutational analysis of the trans-activation-responsive region of the human immunodeficiency virus type 1 long terminal repeat. J Virol 62:673–679;1988.

  48. 48

    Hauber J, Malim M, Cullen B. Mutational analysis of the conserved basic domain of human immunodeficiency virus Tat protein. J Virol 63:1181–1187;1989.

  49. 49

    Haverkos HW, Drotman DP, Morgan M. Prevalence of Kaposi's sarcoma among patients with AIDS. N Engl J Med 312:1518;1985.

  50. 50

    Hayashi SI, Gimble JM, Henley A, Ellingsworth LR, Kincade PW. Differential effects of TGFβ 1 on lymphohemopoiesis in long-term bone marrow cultures. Blood 74:1711–1717;1989.

  51. 51

    Helland DE, Welles JL, Caputo A, Haseltine WA. Transcellular transactivation by the human immunodeficiency virus type 1 Tat protein. J Virol 65:4547–4549;1991.

  52. 52

    Ho DD, Rota TR, Schooley RT, Kaplan JC Jr, Allan D, Groopman JE, Resnick L, Felsenstein D, Andrews CA, Hirsch MS. Isolation of HTLV-III from cerebrospinal fluid and neural tissues of patients with neurologic syndromes related to the acquired immunodeficiency syndrome. N Engl J Med 313:1493–1497;1985.

  53. 53

    Hober D, Haque A, Wattre P, Beaucaire G, Mouton Y, Capron A. Production of tumor necrosis factor α(TNFα) and interleukin-1 (IL-1) in patients with AIDS. Enhanced levels of TNF α is related to a higher cytotoxic activity. Clin Exp Immunol 78:329–333;1989.

  54. 54

    Hofman FM, Wright AD, Dohadwala MM, Wong-Staal F, Walker SM. Exogenous tat protein activates human endothelial cells. Blood 82:2774–2780;1993.

  55. 55

    Howcroft TK, Strebel K, Martin MA, Singer DS. Repression of MHC class I gene promoter activity by two-exon Tat of HIV. Science 260:1320–1322;1993.

  56. 56

    Iwamoto GK, Konicek SA, Twigg HLIII. Modulation of accessory cell function and interleukin-6 production by the HIV-1tat gene. Am J Respir Cell Mol Biol 10:580–585;1994.

  57. 57

    Jelinek DF, Lipsky PE. Inhibitory effects of IL-4 on human B cell responsiveness. J Immunol 141:164–173;1988.

  58. 58

    Jones KA, Kadonaga JT, Luciw PA, Tijan R. Activation of the AIDS retrovirus promoter by the cellular transcription factor Sp1. Science 232:755–759;1986.

  59. 59

    Judware R, Li J, Petryshyn R. Inhibition of the dsRNA-dependent protein kinase by a peptide derived from the human immunodeficiency virus type 1 Tat protein. J Interferon Res 13:153–160;1993.

  60. 60

    Kaplan MH, Susin M, Pahwa SG, Fetten J, Allen SL, Lichtman S, Sarngadharan MG, Gallo RC. Neoplastic complications of HTLV-III infection. Lymphomas and solid tumors. Am J Med 82:389–396;1987.

  61. 61

    Kehrl JH, Alvarez-Mon M, Delsing GA, Fauci AS. Lymphotoxin is an important T cell-derived growth factor for human B cells. Science 242:1144–1146;1987.

  62. 62

    Kekow J, Wachsman W, McCutchan JA, Cronin M, Carson DA, Lotz M. Transforming growth factor β and non-cytopathic mechanisms of immunodeficiency in human immunodeficiency virus infection. Proc Natl Acad Sci USA 87:8321–8325;1990.

  63. 63

    Kim CM, Vogel J, Jay G, Rhim JS. The HIVtat gene transforms human keratinocytes. Oncogene 7:1525–1529;1992.

  64. 64

    Kishimoto T. The biology of IL-6. Blood 74:1–10;1989.

  65. 65

    Knowles DM, Chamulak G, Subar M, Pellicci PG, Dugan M, Burke JS, Raphael B, Dalla-Favera R. Clinicopathologic, immunophenotypic, and molecular genetic analysis of AIDS-associated lymphoid neoplasia. Clinical and biologic implications. Pathol Annu 23:33–67;1988.

  66. 66

    Koenig S, Gendelman HE, Orenstein JM, Dal Canto MC, Pezeshkpour GH, Yungbluth M, Janotta F, Aksamit A, Martin MA, Fauci AS. Detection of AIDS virus in macrophages in brain tissue from AIDS patients with encephalopathy. Science 233:1089–1093;1986.

  67. 67

    Kolson DL, Buchhalter J, Collman R, Hellmig B, Farrell CF, Debouck C, Gonzalez-Scarano F. HIV-1 Tat alters normal organization of neurons and astrocytes in primary rodent brain cell cultures: RGD sequence dependence. AIDS Res Hum Retroviruses 9:677–685;1993.

  68. 68

    Kostura M, Mathews MB. Purification and activation of the double-stranded RNA-dependent eIF-2 kinase DAI. Mol Cell Biol 9:1576–1586;1989.

  69. 69

    Kuppuswamy M, Subramanian T, Srinivasan A, Chinnadurai G. Multiple functional domains of Tat, thetrans-activator of HIV-1 defined by mutational analysis. Nucleic Acids Res 17:3551–3561;1989.

  70. 70

    Lahdevirta J, Maury CPJ, Teppo AM, Repo H. Elevated levels of circulating cachectin/tumor necrosis factor in patients with acquired immunodeficiency syndrome. Am J Med 85:289–291;1988.

  71. 71

    Laurence J, Astrin SM. Human immunodeficiency virus induction of malignant transformation in human B lymphocytes. Proc Natl Acad Sci USA 88:7635–7639;1991.

  72. 72

    Lazdins JK, Klimkait T, Alteri E, Walker M, Woods-Cook K, Cox D, Bilbe G, Shipman R, Cerletti N, McMaster G. TGF-β up-regulator of HIV replication in macrophages. Res Virol 142:239–242;1991.

  73. 73

    Lazdins JK, Klimkait T, Woods-Cook K, Walker M, Alteri E, Cox D, Cerletti N, Shipman R, Bilbe G, McMaster G. In vitro effect of transforming growth factor-β on progression of HIV-1 infection in primary mononuclear phagocytes. J Immunol 147:1201–1207;1991.

  74. 74

    Leeuwenberg JF, Jeunhomme TM, Buurman WA. Induction of an activation antigen on human endothelial cells in vitro. Eur J Immunol 19:715–720;1989.

  75. 75

    Lepe-Zuniga JL, Mansell PWA, Remvig L. Idiopathic production of interleukin-1 in the acquired immunodeficiency syndrome. J Clin Microbiol 25:1695–1700;1987.

  76. 76

    Levin D, London IM. Regulation of protein synthesis: activation by double-stranded RNA of a protein kinase that phosphorylates eukaryotic initiation factor 2. Proc Natl Acad Sci USA 75:1121–1125;1978.

  77. 77

    Lobb RR, Chi-Rosso G, Leone DR, Rosa MD, Bixler S, Newman BA, Lubowsky S, Benjamin CD, Dougas IG, Goelz SE, Hession C, Chow EP. Expression and functional characterization of a soluble form of endothelial leukocyte adhesion molecule 1. J Immunol 147:124–129;1991.

  78. 78

    Locksley RM, Heinzel FP, Shepard HM, Agosti J, Eessalu TE, Aggarwal BB, Harlan JM. Tumor necrosis factors alpha and beta differ in their capacities to generate interleukin 1 release from human endothelial cells. J Immunol 139:1891–1895;1987.

  79. 79

    Lotz M, Kekow J, Cronin MT, McCutchan JA, Clark-Lewis I, Carson DA, Wachsman W. Induction of transforming growth factor-β (TGFβ) by HIV-1 Tat; a noncytopathic pathway of immunodeficiency in HIV infection. FASEB J 4:1861(abstr.);1990.

  80. 80

    Lotz M, Clark-Lewis I, Ganu V. HIV-1 transactivator protein Tat induces proliferation and TGFβ expression in human articular chondrocytes. J Cell Biol 124:365–371;1994.

  81. 81

    Mace K, Gazzolo L. Expression of the Tat protein of HIV1 in human promonocytic U937 cells. Res Virol 144:27–34;1993.

  82. 82

    Marcuzzi A, Weinberger J, Weinberger OK. Transcellular activation of the human immunodeficiency virus type 1 long terminal repeat in cocultured lymphocytes. J Virol 66:4228–4232;1992.

  83. 83

    Matsuyama T, Hamamoto Y, Soma G-I, Mizuno D, Yamamoto N, Kobayashi N. Cytocidal effect of tumor necrosis factor on cells chronically infected with human immunodeficiency virus (HIV): enhancement of HIV replication. J Virol 63:2504–2509;1989.

  84. 84

    Merrick WC. Overview: mechanism of translation initiation in eukaryotes. Enzyme 44:7–16;1990.

  85. 85

    Merrill JE, Chen IS. HIV, macrophages, glial cells, and cytokines in AIDS nervous system disease. FASEB J 5:2391–2397;1991.

  86. 86

    Merrill JE, Koyanagi Y, Chen IS. Interleukin-1 and tumor necrosis factor alpha can be induced from mononuclear phagocytes by human immunodeficiency virus type 1 binding to the CD4 receptor. J Virol 63:4404–4408;1989.

  87. 87

    Milani D, Zauli G, Neri LM, Marchisio M, Previati M, Capitani S. Influence of the human immunodeficiency virus type 1 Tat protein on the proliferation and differentiation of PC12 rat pheochromocytoma cells. J Gen Virol 74:2587–2594;1993.

  88. 88

    Miles SA, Rezai AR, Salazar-Gonzalez JF, VanderMeyden M, Stevens RH, Logan DM, Mitsuyasu RT, Taga T, Kishimoto T, Martinez-Maza O. AIDS Kaposi sarcoma-derived cells produce and respond to interleukin 6. Proc Natl Acad Sci USA 87:4068–4072;1990.

  89. 89

    Mitchell PG, Cheung HS. Tumor necrosis factor alpha and epidermal growth factor regulation of collagenase and stromelysin in adult porcine articular chondrocytes. J Cell Physiol 149:132–140;1991.

  90. 90

    Mueller SG, Paterson AJ, Kudlow JE. Transforming growth factor-α in arterioles: cell surface processing of its precursor by elastases. Mol Cell Biol 10:4596–4602;1990.

  91. 91

    Muesing MA, Smith DH, Capon DJ. Regulation of mRNA accumulation by a human immunodeficiency virus trans-activator protein. Cell 48:691–701;1987.

  92. 92

    Nabell LM, Raja RH, Sayeski PP, Paterson AJ, Kudlow JE. Human immunodeficiency virus 1 Tat stimulates transcription of the transforming growth factor α gene in an epidermal growth factor-dependent manner. Cell Growth Differ 5:87–93;1994.

  93. 93

    Nawroth PP, Bank I, Handley D, Cassimeris J, Chess L, Stein D. Tumor necrosis factor/cachetin interacts with endothelial cell receptors to induce release of interleukin 1. J Exp Med 163:1363–1375;1986.

  94. 94

    Nose K, Shibanuma M, Kikuchi K, Kageyama H, Sakiyama S, Kuroki T. Transcriptional activation of early-response genes by hydrogen peroxide in a mouse osteoblastic cell line. Eur J Biochem 201:99–106;1991.

  95. 95

    Osborn L, Kunkel S, Nabel GJ. Tumor necrosis factor α and interleukin 1 stimulate the human immunodeficiency virus enhancer by activation of the nuclear factor kB. Proc Natl Acad Sci USA 86:2336–2340;1989.

  96. 96

    Paul WE. Interleukin-4: a prototypic immunoregulatory lymphokine. Blood 77:1859–1870;1991.

  97. 97

    Pestka S, Langer JA, Zoon KC, Samuel CE. Interferons and their actions. Annu Rev Biochem 56:727–777;1987.

  98. 98

    Pober JS. Effects of tumor necrosis factor and related cytokines on vascular endothelial cells. Ciba Found Symp 131:170–184;1987.

  99. 99

    Pocsik E, Higuchi M, Aggarwal BB. Down-modulation of cell surface expression of p80 form of the tumor necrosis factor receptor by human immunodeficiency virus-1 tat gene. Lymphokine Cytokine Res 11:317–325;1992.

  100. 100

    Poli G, Bressler P, Kinter A, Duh E, Timmer WC, Rabson A, Justement JS, Stanley S, Fauci AS. Interleukin 6 induces human immunodeficiency virus expression in infected monocytic cells alone and in synergy with tumor necrosis factor α by transcriptional and post-transcriptional mechanisms. J Exp Med 172:151–158;1990.

  101. 101

    Poli G, Kintner A, Justement JS, Kehrl JH, Bressler P, Stanley S, Fauci AS. Tumor necrosis factor α functions in an autocrine manner in the induction of human immunodeficiency virus expression. Proc Natl Acad Sci USA 87:782–785;1990.

  102. 102

    Popovic M, Samgadharan MG, Read E, Gallo RC. Detection, isolation and continuous production of cytopathic retroviruses (HTLV-III) from patients with AIDS and pre-AIDS. Science 224:497–500;1984.

  103. 103

    Pumarola-Sune T, Navia BA, Cordon-Cardo C, Cho ES, Price RW. HIV antigen in the brains of patients with the AIDS dementia complex. Ann Neurol 21:490–496;1987.

  104. 104

    Puri RK, Aggarwal BB. Human immunodeficiency virus type 1tat gene up-regulates interleukin 4 receptors on a human B-lymphoblastoid cell line. Cancer Res 52:3787–3790;1992.

  105. 105

    Purvis SF, Georges DL, Williams TM, Lederman MM. Suppression of interleukin-2 and interleukin-2 receptor expression in Jurkat cells stably expressing the human immunodeficiency virus Tat protein. Cell Immunol 144:32–42;1992.

  106. 106

    Rappaport J, Lee SJ, Khalili K, Wong-Staal F. The acidic amino-terminal region of the HIV-1 Tat protein constitutes an essential activating domain. New Biol 1:101–110;1989.

  107. 107

    Ratner L, Polmar SH, Paul N, Ruddle N. Cytotoxic factors secreted by cells infected by human immunodeficiency virus type 1. AIDS Res Hum Retroviruses 3:147–154;1987.

  108. 108

    Rhim JS, Jay G, Arnstein P, Price FM, Sanford KK, Aaronson SA. Neoplastic transformation of human epidermal keratinocytes by AD12-SV40 and Kirsten sarcoma viruses. Science 227:1250–1252;1985.

  109. 109

    Rieckmann P, Poli G, Fox CH, Kehrl JH, Fauci AS. Recombinant gp120 specifically enhances tumor necrosis factor-alpha production and Ig secretion in B lymphocytes from HIV-infected individuals but not from seronegative donors. J Immunol 147:2922–2927;1991.

  110. 110

    Rosen CA, Sodroski JG, Haseltine WA. The location of cis-acting regulatory sequences in the human T cell lymphotropic virus type III (HTLV-III/LAV) long terminal repeat. Cell 41:813–823;1985.

  111. 111

    Roy S, Delling U, Chen C-H, Rosen CA, Sonenberg N. A bulge structure in HIV-1 TAR RNA is required for tat binding and tatmediated trans-activation. Genes Dev 4:1365–1373;1990.

  112. 112

    Roy S, Katze MG, Parkin NT, Edery I, Hovanessian AG, Sonenberg N. Control of the interferon-induced 68-kilodalton protein kinase by the HIV-1tat gene product. Science 247:1216–1219;1990.

  113. 113

    Roy S, Parkin NT, Rosen C, Itovitch J, Sonenberg N. Structural requirements fortrans activation of human immunodeficiency virus type 1 long terminal repeat-directed gene expression bytat: importance of base pairing, loop sequence, and bulges in thetat-responsive sequence. J Virol 64:1402–1406;1990.

  114. 114

    Roy S, Agy M, Hovanessian AG, Sonenberg N, Katze MG. The integrity of the stem structure of human immunodeficiency virus type 1 tat-responsive sequence RNA is required for interaction with the interferon-induced 68,000 Mr protein kinase. J Virol 65:632–640;1991.

  115. 115

    Ruben S, Perkins A, Purcell R, Joung K, Sia R, Burghoff R, Haseltine W, Rosen C. Structural and functional characterization of human immunodeficiency virus Tat protein. J Virol 63:1–8;1989.

  116. 116

    Ruddle NH, Bergman CM, McGrath KM, Lingenheld EG, Grunnet ML, Padula SJ, Clark RB. An antibody to lymphotoxin and tumor necrosis factor prevents transfer of experimental allergic encephalomyelitis. J Exp Med 172:1193–1200;1990.

  117. 117

    Sabatier J-M, Vives E, Mabrouk K, Benjouad A, Rochat H, Duval A, Hue B, Bahraoui E. Evidence for neurotoxic activity oftat from human immunodeficiency virus type 1. J Virol 65:961–967;1991.

  118. 118

    Safai B, Sarngadharan MG, Groopman JE, Arnett K, Popovic M, Sliski A, Schupbach J, Gallo RC. Seroepidemiological studies of human T-lymphotropic retrovirus type III in acquired immunodeficiency syndrome. Lancet i:1438–1440;1984.

  119. 119

    Sanceau J, Wijdenes J, Revel M, Wietzerbin J. IL-6 and IL-6 receptor modulation by IFN-gamma and tumor necrosis factor-alpha in human monocytic cell line (THP-1). Priming effect of IFN-gamma. J Immunol 147:2630–2637;1991.

  120. 120

    Sariban E, Mitchell T, Kufe D. Expression of the c-fms proto-oncogene during human monocytic differentiation. Nature (London) 316:64–66;1985.

  121. 121

    Sarngadharan MG, Popovich M, Bruch L, Schupbach J, Gallo RC. Antibodies reactive with human T-lymphotropic retroviruses (HTLV-III) in the serum of patients with AIDS. Science 224:506–508;1984.

  122. 122

    Sastry KJ, Reddy RHR, Pandita R, Totpal K, Aggarwal BB. HIV-1tat gene induces tumor necrosis factor-β (lymphotoxin) in a human B-lymphoblastoid cell line. J Biol Chem 265:20091–20093;1990.

  123. 123

    Scala G, Ruocco MR, Ambrosino C, Mallardo M, Giordano V, Baldassarre F, Dragonetti E, Quinto I, Venuta S. The expression of the interleukin 6 gene is induced by the human immunodeficiency virus 1 TAT protein. J Exp Med 179:961–971;1994.

  124. 124

    Schreck R, Rieber P, Baeuerle PA. Reactive oxygen intermediates as apparently widely used messengers in the activation of the NF-kappa B transcription factor and HIV-1. EMBO J 10:2247–2258;1991.

  125. 125

    Scheppler JA, Nicholson JK, Swan DC, Ahmed-Ansari A, McDougal JS. Down-modulation of MHC-I in a CD4+ T cell line, CEM-E5, after HIV-1 infection. J Immunol 143:2858–2866;1989.

  126. 126

    Seigel LJ, Ratner L, Josephs SF, Derse D, Feinberg MB, Reyes GA, O'Brien SJ, Wong-Staal F. Transactivation induced by human T-lymphotropic virus type III (HTLV-III) maps to a viral sequence encoding 58 amino acids and lacks tissue specificity. Virology 148:226–231;1986.

  127. 127

    Sengupta DN, Silverman RH. Activation of interferon-regulated dsRNA-dependent enzymes by human immunodeficiency virus-1 leader RNA. Nucleic Acids Res 17:969–979;1989.

  128. 128

    Sherr CJ, Rettenmeier CW, Sacca R, Roussel MF, Look AT, Stanley ER. The c-fms proto-oncogene product is related to the receptor for the mononuclear phagocyte growth factor, CSF-1. Cell 41:665–676;1985.

  129. 129

    Sodroski JG, Patarca R, Rosen CA, Wong-Staal F, Haseltine WA. Location of the trans-activating region on the genome of human T-cell lymphotropic virus type III. Science 229:74–77;1985.

  130. 130

    Steffy K, Wong-Staal F. Genetic regulation of human immunodeficiency virus. Microbiol Rev 55:193–205;1991.

  131. 131

    Subramanyam M, Gutheil WG, Bachovchin WW, Huber BT. Mechanism of HIV-1 Tat induced inhibition of antigen-specific T cell responsiveness. J Immunol 150:2544–2553;1993.

  132. 132

    Taylor JP, Cupp C, Diaz A, Chowdhury M, Khalili K, Jimenez SA, Amini S. Activation of expression of genes coding for extracellular matrix proteins in Tat-producing glioblastoma cells. Proc Natl Acad Sci USA 89:9617–9621;1992.

  133. 133

    Taylor JP, Pomerantz R, Bagasra O, Chowdhury M, Rappaport J, Khalili K, Amini S. TAR-independent transactivation by Tat in cells derived from the CNS: a novel mechanism of HIV-1 gene regulation. EMBO J 11:3395–3403;1992.

  134. 134

    Te Velde AA, Huijbens RJF, Heije K, de Vries JE, Figdor CG. IL-4 inhibits secretion of IL-1β, tumor necrosis factor α, and IL-6 by human monocytes. Blood 76:1392–1397;1990.

  135. 135

    Townsend A, Bodmer H. Antigen recognition by class I-restricted T lymphocytes. Annu Rev Immunol 7:601–624;1989.

  136. 136

    Ursini MV, Lettieri T, Braddock M, Martini G. Enhanced activity of human G6PD promoter transfected in HeLa cells producing high levels of HIV-1 Tat. Virology 196:338–343;1993.

  137. 137

    Vercelli D, Jabara HH, Lauener RP, Geha RS. IL-4 inhibits the synthesis of IFN-γ and induces the synthesis of IgE in human mixed cultures. J Immunol 144:570–573;1990.

  138. 138

    Viscidi RP, Mayur K, Lederman HM, Frankel AD. Inhibition of antigen-induced lymphocyte proliferation by Tat protein from HIV-1. Science 246:1606–1608;1989.

  139. 139

    Visvader J, Verma IM. Differential transcription of exon 1 of the human c-fms gene in placental trophoblasts and monocytes. Mol Cell Biol 9:1336–1341;1989.

  140. 140

    Vogel J, Hinrichs SH, Reynolds RK, Luciw PA, Jay G. The HIVtat gene induces dermal lesions resembling Kaposi's sarcoma in transgenic mice. Nature (London) 335:606–611;1988.

  141. 141

    Wahl SM, Hunt DA, Wakefield LM, McCartney-Francis N, Wahl LM, Roberts AB, Sporn MB. Transforming growth factor type beta induces monocyte chemotaxis and growth factor production. Proc Natl Acad Sci USA 84:5788–5792;1987.

  142. 142

    Wahl LM, Corcoran ML, Pyle SW, Arthur LO, Harel-Bellan A, Farrar WL. Human immunodeficiency virus glycoprotein (gp120) induction of monocyte arachidonic acid metabolites and interleukin 1. Proc Natl Acad Sci USA 86:621–625;1989.

  143. 143

    Wahl SM, Allen JB, McCartney-Francis N, Morganti-Kossmann MC, Kossmann T, Ellingsworth L, Mai UEH, Mergenhagen SE, Orenstein JM. Macrophage- and astrocyte-derived transforming growth factor beta as a mediator of central nervous system dysfunction in acquired immune deficiency syndrome. J Exp Med 173:981–991;1991.

  144. 144

    Weeks BS, Klotman ME, Holloway E, Stetler-Stevenson WG, Kleinman HK, Klotman PE. HIV-1 infection stimulates T cell invasiveness and synthesis of the 92-kDa type IV collagenase. AIDS Res Hum Retroviruses 9:513–518;1993.

  145. 145

    Westendorp MO, Li-Weber M, Frank RW, Krammer PH. Human immunodeficiency virus type 1 Tat upregulates interleukin-2 secretion in activated T cells. J Virol 68:4177–4185;1994.

  146. 146

    Widmer MB, Acres RB, Sassenfield NM, Grabstein KH. Regulation of cytolytic cell populations from human peripheral blood by B cell stimulatory factor 1 (interleukin 4). J Exp Med 166:1447–1452;1987.

  147. 147

    Wiley CA, Nelson JA. Role of human immunodeficiency virus and cytomegalovirus in AIDS encephalitis. Am J Pathol 133:73–81;1988.

  148. 148

    Wong GH, McHugh T, Weber R, Goeddel DV. Tumor necrosis factor alpha selectively sensitizes human immunodeficiency virus-infected cells to heat and radiation. Proc Natl Acad Sci USA 88:4372–4376;1991.

  149. 149

    Zauli G, Davis BR, Re MC, Visani G, Furlini G, La Placa M. Tat protein stimulates production of transforming growth factor-β 1 by marrow macrophages: a potential mechanism for human immunodeficiency virus-1-induced hematopoietic suppression. Blood 80:3036–3043;1992.

  150. 150

    Zauli G, Furlini G, Re MC, Milani D, Capitani S, La Placa M. Human immunodeficiency virus type 1 (HIV-1) Tat-protein stimulates the production of interleukin-6 (IL-6) by peripheral blood monocytes. Microbiologica 16:115–120;1993.

  151. 151

    Zauli G, Gibellini D, Milani D, Mazzoni M, Borgatti P, La Placa M, Capitani S. Human immunodeficiency virus type 1 Tat protein protects lymphoid, epithelial, and neuronal cell lines from death by apoptosis. Cancer Res 53:4481–4485;1993.

Download references

Author information

Rights and permissions

Reprints and Permissions

About this article

Cite this article

Chang, H., Gallo, R.C. & Ensoli, B. Regulation of cellular gene expression and function by the human immunodeficiency virus type 1 tat protein. J Biomed Sci 2, 189–202 (1995).

Download citation

Key words

  • HIV-1
  • Tat
  • Transactivation
  • Cytokine genes
  • Extracellular matrix proteins
  • Cell growth
  • Angiogenesis
  • Tumorigenesis