Logo of jvirolPermissionsJournals.ASM.orgJournalJV ArticleJournal InfoAuthorsReviewers
J Virol. Dec 1992; 66(12): 7159–7167.
PMCID: PMC240407

Effects of the human immunodeficiency virus type 1 Tat protein on the expression of inflammatory cytokines.

Abstract

Increased levels of inflammatory cytokines, including tumor necrosis factor (TNF), interleukin-1 (IL-1), and IL-6, have been detected in specimens from human immunodeficiency virus type 1 (HIV-1)-infected individuals. Here we demonstrate that HIV-1 activates the expression of TNF but not of IL-1 and IL-6 in acutely and chronically infected T cells. The increase in TNF gene expression is due to activation of the TNF promoter by the viral gene product Tat. Transactivation of TNF gene expression requires the product of the first exon of the tat gene and is cell type independent. T cells chronically infected with pol-defective HIV-1 provirus constitutively express both Tat and TNF at levels significantly higher (fivefold) than those seen in control cells, and treatment with phorbol myristate acetate greatly enhances Tat expression and TNF production. As TNF can increase the production of IL-1 and IL-6 and these inflammatory cytokines all enhance HIV-1 gene expression and affect the immune, vascular, and central nervous systems, the activation of TNF by Tat may be part of a complex pathway in which HIV-1 uses viral products and host factors to increase its own expression and infectivity and to induce disease.

Full text

Full text is available as a scanned copy of the original print version. Get a printable copy (PDF file) of the complete article (2.0M), or click on a page image below to browse page by page. Links to PubMed are also available for Selected References.

Images in this article

Selected References

These references are in PubMed. This may not be the complete list of references from this article.
  • Aboulafia D, Miles SA, Saks SR, Mitsuyasu RT. Intravenous recombinant tumor necrosis factor in the treatment of AIDS-related Kaposi's sarcoma. J Acquir Immune Defic Syndr. 1989;2(1):54–58. [PubMed]
  • Arya SK, Guo C, Josephs SF, Wong-Staal F. Trans-activator gene of human T-lymphotropic virus type III (HTLV-III). Science. 1985 Jul 5;229(4708):69–73. [PubMed]
  • 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. 1990 Aug 24;62(4):757–767. [PubMed]
  • Boulerice F, Bour S, Geleziunas R, Lvovich A, Wainberg MA. High frequency of isolation of defective human immunodeficiency virus type 1 and heterogeneity of viral gene expression in clones of infected U-937 cells. J Virol. 1990 Apr;64(4):1745–1755. [PMC free article] [PubMed]
  • Boulter CA, Wagner EF. A universal retroviral vector for efficient constitutive expression of exogenous genes. Nucleic Acids Res. 1987 Sep 11;15(17):7194–7194. [PMC free article] [PubMed]
  • 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. 1990 Jan 15;144(2):480–484. [PubMed]
  • Cicco NA, Lübbert M, Oster W, Lindemann A, Mertelsmann R. Cytokines in the pathogenesis and management of non-Hodgkin's lymphomas. Hematol Oncol Clin North Am. 1991 Oct;5(5):1053–1066. [PubMed]
  • Clouse KA, Powell D, Washington I, Poli G, Strebel K, Farrar W, Barstad P, Kovacs J, Fauci AS, Folks TM. Monokine regulation of human immunodeficiency virus-1 expression in a chronically infected human T cell clone. J Immunol. 1989 Jan 15;142(2):431–438. [PubMed]
  • Clouse KA, Robbins PB, Fernie B, Ostrove JM, Fauci AS. Viral antigen stimulation of the production of human monokines capable of regulating HIV1 expression. J Immunol. 1989 Jul 15;143(2):470–475. [PubMed]
  • Cross SL, Feinberg MB, Wolf JB, Holbrook NJ, Wong-Staal F, Leonard WJ. Regulation of the human interleukin-2 receptor alpha chain promoter: activation of a nonfunctional promoter by the transactivator gene of HTLV-I. Cell. 1987 Apr 10;49(1):47–56. [PubMed]
  • Dayton AI, Sodroski JG, Rosen CA, Goh WC, Haseltine WA. The trans-activator gene of the human T cell lymphotropic virus type III is required for replication. Cell. 1986 Mar 28;44(6):941–947. [PubMed]
  • Dinarello CA, Savage N. Interleukin-1 and its receptor. Crit Rev Immunol. 1989;9(1):1–20. [PubMed]
  • Ensoli B, Barillari G, Gallo RC. Pathogenesis of AIDS-associated Kaposi's sarcoma. Hematol Oncol Clin North Am. 1991 Apr;5(2):281–295. [PubMed]
  • 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. 1990 May 3;345(6270):84–86. [PubMed]
  • Ensoli B, Lusso P, Schachter F, Josephs SF, Rappaport J, Negro F, Gallo RC, Wong-Staal F. Human herpes virus-6 increases HIV-1 expression in co-infected T cells via nuclear factors binding to the HIV-1 enhancer. EMBO J. 1989 Oct;8(10):3019–3027. [PMC free article] [PubMed]
  • Ensoli B, Nakamura S, Salahuddin SZ, Biberfeld P, Larsson L, Beaver B, Wong-Staal F, Gallo RC. AIDS-Kaposi's sarcoma-derived cells express cytokines with autocrine and paracrine growth effects. Science. 1989 Jan 13;243(4888):223–226. [PubMed]
  • Fauci AS. The human immunodeficiency virus: infectivity and mechanisms of pathogenesis. Science. 1988 Feb 5;239(4840):617–622. [PubMed]
  • Felber BK, Paskalis H, Kleinman-Ewing C, Wong-Staal F, Pavlakis GN. The pX protein of HTLV-I is a transcriptional activator of its long terminal repeats. Science. 1985 Aug 16;229(4714):675–679. [PubMed]
  • Feng S, Holland EC. HIV-1 tat trans-activation requires the loop sequence within tar. Nature. 1988 Jul 14;334(6178):165–167. [PubMed]
  • Fisher AG, Feinberg MB, Josephs SF, Harper ME, Marselle LM, Reyes G, Gonda MA, Aldovini A, Debouk C, Gallo RC, et al. The trans-activator gene of HTLV-III is essential for virus replication. Nature. 320(6060):367–371. [PubMed]
  • Folks TM, Justement J, Kinter A, Dinarello CA, Fauci AS. Cytokine-induced expression of HIV-1 in a chronically infected promonocyte cell line. Science. 1987 Nov 6;238(4828):800–802. [PubMed]
  • Folks TM, Powell D, Lightfoote M, Koenig S, Fauci AS, Benn S, Rabson A, Daugherty D, Gendelman HE, Hoggan MD, et al. Biological and biochemical characterization of a cloned Leu-3- cell surviving infection with the acquired immune deficiency syndrome retrovirus. J Exp Med. 1986 Jul 1;164(1):280–290. [PMC free article] [PubMed]
  • Frankel AD, Pabo CO. Cellular uptake of the tat protein from human immunodeficiency virus. Cell. 1988 Dec 23;55(6):1189–1193. [PubMed]
  • 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. 1989 Mar;8(3):765–778. [PMC free article] [PubMed]
  • Gorman CM, Moffat LF, Howard BH. Recombinant genomes which express chloramphenicol acetyltransferase in mammalian cells. Mol Cell Biol. 1982 Sep;2(9):1044–1051. [PMC free article] [PubMed]
  • Griffin GE, Leung K, Folks TM, Kunkel S, Nabel GJ. Activation of HIV gene expression during monocyte differentiation by induction of NF-kappa B. Nature. 1989 May 4;339(6219):70–73. [PubMed]
  • Gruters RA, Otto SA, Al BJ, Verhoeven AJ, Verweij CL, Van Lier RA, Miedema F. Non-mitogenic T cell activation signals are sufficient for induction of human immunodeficiency virus transcription. Eur J Immunol. 1991 Jan;21(1):167–172. [PubMed]
  • Inoue J, Seiki M, Taniguchi T, Tsuru S, Yoshida M. Induction of interleukin 2 receptor gene expression by p40x encoded by human T-cell leukemia virus type 1. EMBO J. 1986 Nov;5(11):2883–2888. [PMC free article] [PubMed]
  • Jeang KT, Shank PR, Kumar A. Transcriptional activation of homologous viral long terminal repeats by the human immunodeficiency virus type 1 or the human T-cell leukemia virus type I tat proteins occurs in the absence of de novo protein synthesis. Proc Natl Acad Sci U S A. 1988 Nov;85(21):8291–8295. [PMC free article] [PubMed]
  • Johnson RT, McArthur JC, Narayan O. The neurobiology of human immunodeficiency virus infections. FASEB J. 1988 Nov;2(14):2970–2981. [PubMed]
  • Jones KA, Kadonaga JT, Luciw PA, Tjian R. Activation of the AIDS retrovirus promoter by the cellular transcription factor, Sp1. Science. 1986 May 9;232(4751):755–759. [PubMed]
  • Kao SY, Calman AF, Luciw PA, Peterlin BM. Anti-termination of transcription within the long terminal repeat of HIV-1 by tat gene product. Nature. 1987 Dec 3;330(6147):489–493. [PubMed]
  • Kehrl JH, Alvarez-Mon M, Delsing GA, Fauci AS. Lymphotoxin is an important T cell-derived growth factor for human B cells. Science. 1987 Nov 20;238(4830):1144–1146. [PubMed]
  • Kim SJ, Kehrl JH, Burton J, Tendler CL, Jeang KT, Danielpour D, Thevenin C, Kim KY, Sporn MB, Roberts AB. Transactivation of the transforming growth factor beta 1 (TGF-beta 1) gene by human T lymphotropic virus type 1 tax: a potential mechanism for the increased production of TGF-beta 1 in adult T cell leukemia. J Exp Med. 1990 Jul 1;172(1):121–129. [PMC free article] [PubMed]
  • Kishimoto T, Hirano T. Molecular regulation of B lymphocyte response. Annu Rev Immunol. 1988;6:485–512. [PubMed]
  • Knight DM, Flomerfelt FA, Ghrayeb J. Expression of the art/trs protein of HIV and study of its role in viral envelope synthesis. Science. 1987 May 15;236(4803):837–840. [PubMed]
  • Leonard J, Parrott C, Buckler-White AJ, Turner W, Ross EK, Martin MA, Rabson AB. The NF-kappa B binding sites in the human immunodeficiency virus type 1 long terminal repeat are not required for virus infectivity. J Virol. 1989 Nov;63(11):4919–4924. [PMC free article] [PubMed]
  • Lepe-Zuniga JL, Mansell PW, Hersh EM. Idiopathic production of interleukin-1 in acquired immune deficiency syndrome. J Clin Microbiol. 1987 Sep;25(9):1695–1700. [PMC free article] [PubMed]
  • Lifson AR, Rutherford GW, Jaffe HW. The natural history of human immunodeficiency virus infection. J Infect Dis. 1988 Dec;158(6):1360–1367. [PubMed]
  • Lindholm PF, Reid RL, Brady JN. Extracellular Tax1 protein stimulates tumor necrosis factor-beta and immunoglobulin kappa light chain expression in lymphoid cells. J Virol. 1992 Mar;66(3):1294–1302. [PMC free article] [PubMed]
  • 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. 1987 Sep 15;139(6):1891–1895. [PubMed]
  • 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. 1989 Oct;63(10):4404–4408. [PMC free article] [PubMed]
  • Meyerhans A, Cheynier R, Albert J, Seth M, Kwok S, Sninsky J, Morfeldt-Månson L, Asjö B, Wain-Hobson S. Temporal fluctuations in HIV quasispecies in vivo are not reflected by sequential HIV isolations. Cell. 1989 Sep 8;58(5):901–910. [PubMed]
  • Miles SA, Rezai AR, Salazar-González JF, Vander Meyden M, Stevens RH, Logan DM, Mitsuyasu RT, Taga T, Hirano T, Kishimoto T, et al. AIDS Kaposi sarcoma-derived cells produce and respond to interleukin 6. Proc Natl Acad Sci U S A. 1990 Jun;87(11):4068–4072. [PMC free article] [PubMed]
  • Miller AD, Rosman GJ. Improved retroviral vectors for gene transfer and expression. Biotechniques. 1989 Oct;7(9):980–990. [PMC free article] [PubMed]
  • Nabel G, Baltimore D. An inducible transcription factor activates expression of human immunodeficiency virus in T cells. Nature. 1987 Apr 16;326(6114):711–713. [PubMed]
  • Nedwin GE, Naylor SL, Sakaguchi AY, Smith D, Jarrett-Nedwin J, Pennica D, Goeddel DV, Gray PW. Human lymphotoxin and tumor necrosis factor genes: structure, homology and chromosomal localization. Nucleic Acids Res. 1985 Sep 11;13(17):6361–6373. [PMC free article] [PubMed]
  • Parrott C, Seidner T, Duh E, Leonard J, Theodore TS, Buckler-White A, Martin MA, Rabson AB. Variable role of the long terminal repeat Sp1-binding sites in human immunodeficiency virus replication in T lymphocytes. J Virol. 1991 Mar;65(3):1414–1419. [PMC free article] [PubMed]
  • Paul NL, Ruddle NH. Lymphotoxin. Annu Rev Immunol. 1988;6:407–438. [PubMed]
  • Poli G, Kinter A, Justement JS, Kehrl JH, Bressler P, Stanley S, Fauci AS. Tumor necrosis factor alpha functions in an autocrine manner in the induction of human immunodeficiency virus expression. Proc Natl Acad Sci U S A. 1990 Jan;87(2):782–785. [PMC free article] [PubMed]
  • Quinnan GV, Jr, Rook AH, Frederick WR, Manischewitz JF, Epstein JS, Siegel J, Masur H, Macher AM, Mitchell C, Armstrong G, et al. Prevalence, clinical manifestations, and immunology of herpesvirus infections in the acquired immunodeficiency syndrome. Ann N Y Acad Sci. 1984;437:200–206. [PubMed]
  • Ratner L, Polmar SH, Paul N, Ruddle N. Cytotoxic factors secreted by cells infected by human immunodeficiency virus type I. AIDS Res Hum Retroviruses. 1987 Summer;3(2):147–155. [PubMed]
  • Remenick J, Radonovich MF, Brady JN. Human immunodeficiency virus Tat transactivation: induction of a tissue-specific enhancer in a nonpermissive cell line. J Virol. 1991 Oct;65(10):5641–5646. [PMC free article] [PubMed]
  • Rice AP, Mathews MB. Transcriptional but not translational regulation of HIV-1 by the tat gene product. Nature. 1988 Apr 7;332(6164):551–553. [PubMed]
  • 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. 1991 Nov 1;147(9):2922–2927. [PubMed]
  • 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. 1985 Jul;41(3):813–823. [PubMed]
  • 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. 1990 Oct 1;172(4):1193–1200. [PMC free article] [PubMed]
  • Sadaie MR, Tschachler E, Valerie K, Rosenberg M, Felber BK, Pavlakis GN, Klotman ME, Wong-Staal F. Activation of tat-defective human immunodeficiency virus by ultraviolet light. New Biol. 1990 May;2(5):479–486. [PubMed]
  • Saiki RK, Scharf S, Faloona F, Mullis KB, Horn GT, Erlich HA, Arnheim N. Enzymatic amplification of beta-globin genomic sequences and restriction site analysis for diagnosis of sickle cell anemia. Science. 1985 Dec 20;230(4732):1350–1354. [PubMed]
  • Salahuddin SZ, Markham PD, Wong-Staal F, Franchini G, Kalyanaraman VS, Gallo RC. Restricted expression of human T-cell leukemia--lymphoma virus (HTLV) in transformed human umbilical cord blood lymphocytes. Virology. 1983 Aug;129(1):51–64. [PubMed]
  • 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. 1991 Oct 15;147(8):2630–2637. [PubMed]
  • Sastry KJ, Reddy HR, Pandita R, Totpal K, Aggarwal BB. HIV-1 tat gene induces tumor necrosis factor-beta (lymphotoxin) in a human B-lymphoblastoid cell line. J Biol Chem. 1990 Nov 25;265(33):20091–20093. [PubMed]
  • Seigel LJ, Ratner L, Josephs SF, Derse D, Feinberg MB, Reyes GR, 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. 1986 Jan 15;148(1):226–231. [PubMed]
  • Shearer GM, Levy RB. Noninfectious cofactors in susceptibility to AIDS: possible contributions of semen, HLA alloantigens, and lack of natural resistance. Ann N Y Acad Sci. 1984;437:49–57. [PubMed]
  • Siekevitz M, Josephs SF, Dukovich M, Peffer N, Wong-Staal F, Greene WC. Activation of the HIV-1 LTR by T cell mitogens and the trans-activator protein of HTLV-I. Science. 1987 Dec 11;238(4833):1575–1578. [PubMed]
  • Sodroski J, Patarca R, Rosen C, Wong-Staal F, Haseltine W. Location of the trans-activating region on the genome of human T-cell lymphotropic virus type III. Science. 1985 Jul 5;229(4708):74–77. [PubMed]
  • Tada H, Rappaport J, Lashgari M, Amini S, Wong-Staal F, Khalili K. Trans-activation of the JC virus late promoter by the tat protein of type 1 human immunodeficiency virus in glial cells. Proc Natl Acad Sci U S A. 1990 May;87(9):3479–3483. [PMC free article] [PubMed]
  • Tong-Starksen SE, Luciw PA, Peterlin BM. Human immunodeficiency virus long terminal repeat responds to T-cell activation signals. Proc Natl Acad Sci U S A. 1987 Oct;84(19):6845–6849. [PMC free article] [PubMed]
  • Tschachler E, Robert-Guroff M, Gallo RC, Reitz MS., Jr Human T-lymphotropic virus I-infected T cells constitutively express lymphotoxin in vitro. Blood. 1989 Jan;73(1):194–201. [PubMed]
  • 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 U S A. 1989 Jan;86(2):621–625. [PMC free article] [PubMed]
  • Wano Y, Feinberg M, Hosking JB, Bogerd H, Greene WC. Stable expression of the tax gene of type I human T-cell leukemia virus in human T cells activates specific cellular genes involved in growth. Proc Natl Acad Sci U S A. 1988 Dec;85(24):9733–9737. [PMC free article] [PubMed]
  • Zagury D, Bernard J, Leonard R, Cheynier R, Feldman M, Sarin PS, Gallo RC. Long-term cultures of HTLV-III--infected T cells: a model of cytopathology of T-cell depletion in AIDS. Science. 1986 Feb 21;231(4740):850–853. [PubMed]

Articles from Journal of Virology are provided here courtesy of American Society for Microbiology (ASM)

Formats:

Related citations in PubMed

See reviews...See all...

Cited by other articles in PMC

See all...

Links

Recent Activity

Your browsing activity is empty.

Activity recording is turned off.

Turn recording back on

See more...