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J Clin Invest. May 1995; 95(5): 2324–2331.
PMCID: PMC295846

Mycobacterium tuberculosis enhances human immunodeficiency virus-1 replication by transcriptional activation at the long terminal repeat.

Abstract

Tuberculosis has emerged as an epidemic fueled by the large number of individuals infected with the human immunodeficiency virus, especially those who are injecting drug users. We found a striking increase from 4- to 208-fold in p24 levels in bronchoalveolar lavage fluid from involved sites of Mycobacterium tuberculosis infection vs uninvolved sites in three HIV+ patients. We used an in vitro cell culture model to determine if tuberculosis could activate replication of HIV-1. Mononuclear phagocyte cell lines U937 and THP-1 infected with HIV-1JR-CSF, in vitro and stimulated with live M. tuberculosis H37Ra, had a threefold increase in p24 in culture supernatants. Using the HIV-1 long terminal repeat with a chloramphenicol acetyltransferase (CAT) reporter construct, live M. tuberculosis increased transcription 20-fold in THP-1 cells, and cell wall components stimulated CAT expression to a lesser extent. The nuclear factor-kappa B enhancer element was responsible for the majority of the increased CAT activity although two upstream nuclear factor-IL6 sites may also contribute to enhanced transcription. Antibodies to TNF-alpha and IL-1 inhibited the increase in CAT activity of the HIV-1 long terminal repeat by M. tuberculosis from 21-fold to 8-fold. Stimulation of HIV-1 replication by M. tuberculosis may exacerbate dysfunction of the host immune response in dually infected individuals.

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  • Bloom BR, Murray CJ. Tuberculosis: commentary on a reemergent killer. Science. 1992 Aug 21;257(5073):1055–1064. [PubMed]
  • Barnes PF, Bloch AB, Davidson PT, Snider DE., Jr Tuberculosis in patients with human immunodeficiency virus infection. N Engl J Med. 1991 Jun 6;324(23):1644–1650. [PubMed]
  • Theuer CP, Hopewell PC, Elias D, Schecter GF, Rutherford GW, Chaisson RE. Human immunodeficiency virus infection in tuberculosis patients. J Infect Dis. 1990 Jul;162(1):8–12. [PubMed]
  • Pitchenik AE, Burr J, Suarez M, Fertel D, Gonzalez G, Moas C. Human T-cell lymphotropic virus-III (HTLV-III) seropositivity and related disease among 71 consecutive patients in whom tuberculosis was diagnosed. A prospective study. Am Rev Respir Dis. 1987 Apr;135(4):875–879. [PubMed]
  • Chaisson RE, Schecter GF, Theuer CP, Rutherford GW, Echenberg DF, Hopewell PC. Tuberculosis in patients with the acquired immunodeficiency syndrome. Clinical features, response to therapy, and survival. Am Rev Respir Dis. 1987 Sep;136(3):570–574. [PubMed]
  • Selwyn PA, Hartel D, Lewis VA, Schoenbaum EE, Vermund SH, Klein RS, Walker AT, Friedland GH. A prospective study of the risk of tuberculosis among intravenous drug users with human immunodeficiency virus infection. N Engl J Med. 1989 Mar 2;320(9):545–550. [PubMed]
  • Hill AR, Premkumar S, Brustein S, Vaidya K, Powell S, Li PW, Suster B. Disseminated tuberculosis in the acquired immunodeficiency syndrome era. Am Rev Respir Dis. 1991 Nov;144(5):1164–1170. [PubMed]
  • Shafer RW, Kim DS, Weiss JP, Quale JM. Extrapulmonary tuberculosis in patients with human immunodeficiency virus infection. Medicine (Baltimore) 1991 Nov;70(6):384–397. [PubMed]
  • Jones BE, Young SM, Antoniskis D, Davidson PT, Kramer F, Barnes PF. Relationship of the manifestations of tuberculosis to CD4 cell counts in patients with human immunodeficiency virus infection. Am Rev Respir Dis. 1993 Nov;148(5):1292–1297. [PubMed]
  • Daley CL, Small PM, Schecter GF, Schoolnik GK, McAdam RA, Jacobs WR, Jr, Hopewell PC. An outbreak of tuberculosis with accelerated progression among persons infected with the human immunodeficiency virus. An analysis using restriction-fragment-length polymorphisms. N Engl J Med. 1992 Jan 23;326(4):231–235. [PubMed]
  • Eriki PP, Okwera A, Aisu T, Morrissey AB, Ellner JJ, Daniel TM. The influence of human immunodeficiency virus infection on tuberculosis in Kampala, Uganda. Am Rev Respir Dis. 1991 Jan;143(1):185–187. [PubMed]
  • Frieden TR, Sterling T, Pablos-Mendez A, Kilburn JO, Cauthen GM, Dooley SW. The emergence of drug-resistant tuberculosis in New York City. N Engl J Med. 1993 Feb 25;328(8):521–526. [PubMed]
  • Toossi Z, Sierra-Madero JG, Blinkhorn RA, Mettler MA, Rich EA. Enhanced susceptibility of blood monocytes from patients with pulmonary tuberculosis to productive infection with human immunodeficiency virus type 1. J Exp Med. 1993 May 1;177(5):1511–1516. [PMC free article] [PubMed]
  • Takashima T, Ueta C, Tsuyuguchi I, Kishimoto S. Production of tumor necrosis factor alpha by monocytes from patients with pulmonary tuberculosis. Infect Immun. 1990 Oct;58(10):3286–3292. [PMC free article] [PubMed]
  • Moreno C, Taverne J, Mehlert A, Bate CA, Brealey RJ, Meager A, Rook GA, Playfair JH. Lipoarabinomannan from Mycobacterium tuberculosis induces the production of tumour necrosis factor from human and murine macrophages. Clin Exp Immunol. 1989 May;76(2):240–245. [PMC free article] [PubMed]
  • Chensue SW, Davey MP, Remick DG, Kunkel SL. Release of interleukin-1 by peripheral blood mononuclear cells in patients with tuberculosis and active inflammation. Infect Immun. 1986 Apr;52(1):341–343. [PMC free article] [PubMed]
  • Wallis RS, Fujiwara H, Ellner JJ. Direct stimulation of monocyte release of interleukin 1 by mycobacterial protein antigens. J Immunol. 1986 Jan;136(1):193–196. [PubMed]
  • Wallis RS, Amir-Tahmasseb M, Ellner JJ. Induction of interleukin 1 and tumor necrosis factor by mycobacterial proteins: the monocyte western blot. Proc Natl Acad Sci U S A. 1990 May;87(9):3348–3352. [PMC free article] [PubMed]
  • Barnes PF, Chatterjee D, Abrams JS, Lu S, Wang E, Yamamura M, Brennan PJ, Modlin RL. Cytokine production induced by Mycobacterium tuberculosis lipoarabinomannan. Relationship to chemical structure. J Immunol. 1992 Jul 15;149(2):541–547. [PubMed]
  • Kindler V, Sappino AP, Grau GE, Piguet PF, Vassalli P. The inducing role of tumor necrosis factor in the development of bactericidal granulomas during BCG infection. Cell. 1989 Mar 10;56(5):731–740. [PubMed]
  • Zhang Y, Doerfler M, Lee TC, Guillemin B, Rom WN. Mechanisms of stimulation of interleukin-1 beta and tumor necrosis factor-alpha by Mycobacterium tuberculosis components. J Clin Invest. 1993 May;91(5):2076–2083. [PMC free article] [PubMed]
  • Ogawa T, Uchida H, Kusumoto Y, Mori Y, Yamamura Y, Hamada S. Increase in tumor necrosis factor alpha- and interleukin-6-secreting cells in peripheral blood mononuclear cells from subjects infected with Mycobacterium tuberculosis. Infect Immun. 1991 Sep;59(9):3021–3025. [PMC free article] [PubMed]
  • Schauf V, Rom WN, Smith KA, Sampaio EP, Meyn PA, Tramontana JM, Cohn ZA, Kaplan G. Cytokine gene activation and modified responsiveness to interleukin-2 in the blood of tuberculosis patients. J Infect Dis. 1993 Oct;168(4):1056–1059. [PubMed]
  • Koyanagi Y, O'Brien WA, Zhao JQ, Golde DW, Gasson JC, Chen IS. Cytokines alter production of HIV-1 from primary mononuclear phagocytes. Science. 1988 Sep 23;241(4873):1673–1675. [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]
  • Osborn L, Kunkel S, Nabel GJ. Tumor necrosis factor alpha and interleukin 1 stimulate the human immunodeficiency virus enhancer by activation of the nuclear factor kappa B. Proc Natl Acad Sci U S A. 1989 Apr;86(7):2336–2340. [PMC free article] [PubMed]
  • Duh EJ, Maury WJ, Folks TM, Fauci AS, Rabson AB. Tumor necrosis factor alpha activates human immunodeficiency virus type 1 through induction of nuclear factor binding to the NF-kappa B sites in the long terminal repeat. Proc Natl Acad Sci U S A. 1989 Aug;86(15):5974–5978. [PMC free article] [PubMed]
  • Rosenberg ZF, Fauci AS. Immunopathogenesis of HIV infection. FASEB J. 1991 Jul;5(10):2382–2390. [PubMed]
  • Greene WC. The molecular biology of human immunodeficiency virus type 1 infection. N Engl J Med. 1991 Jan 31;324(5):308–317. [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]
  • 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]
  • Prinzis S, Chatterjee D, Brennan PJ. Structure and antigenicity of lipoarabinomannan from Mycobacterium bovis BCG. J Gen Microbiol. 1993 Nov;139(11):2649–2658. [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]
  • Dignam JD, Lebovitz RM, Roeder RG. Accurate transcription initiation by RNA polymerase II in a soluble extract from isolated mammalian nuclei. Nucleic Acids Res. 1983 Mar 11;11(5):1475–1489. [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]
  • Sen R, Baltimore D. Inducibility of kappa immunoglobulin enhancer-binding protein Nf-kappa B by a posttranslational mechanism. Cell. 1986 Dec 26;47(6):921–928. [PubMed]
  • Berenguer J, Moreno S, Laguna F, Vicente T, Adrados M, Ortega A, González-LaHoz J, Bouza E. Tuberculous meningitis in patients infected with the human immunodeficiency virus. N Engl J Med. 1992 Mar 5;326(10):668–672. [PubMed]
  • Rennard SI, Basset G, Lecossier D, O'Donnell KM, Pinkston P, Martin PG, Crystal RG. Estimation of volume of epithelial lining fluid recovered by lavage using urea as marker of dilution. J Appl Physiol (1985) 1986 Feb;60(2):532–538. [PubMed]
  • Zhang Y, Rom WN. Regulation of the interleukin-1 beta (IL-1 beta) gene by mycobacterial components and lipopolysaccharide is mediated by two nuclear factor-IL6 motifs. Mol Cell Biol. 1993 Jun;13(6):3831–3837. [PMC free article] [PubMed]
  • Zhang Y, Broser M, Rom WN. Activation of the interleukin 6 gene by Mycobacterium tuberculosis or lipopolysaccharide is mediated by nuclear factors NF-IL6 and NF-kappa B. Proc Natl Acad Sci U S A. 1994 Mar 15;91(6):2225–2229. [PMC free article] [PubMed]
  • Matsusaka T, Fujikawa K, Nishio Y, Mukaida N, Matsushima K, Kishimoto T, Akira S. Transcription factors NF-IL6 and NF-kappa B synergistically activate transcription of the inflammatory cytokines, interleukin 6 and interleukin 8. Proc Natl Acad Sci U S A. 1993 Nov 1;90(21):10193–10197. [PMC free article] [PubMed]
  • Stein B, Baldwin AS., Jr Distinct mechanisms for regulation of the interleukin-8 gene involve synergism and cooperativity between C/EBP and NF-kappa B. Mol Cell Biol. 1993 Nov;13(11):7191–7198. [PMC free article] [PubMed]
  • Pope RM, Leutz A, Ness SA. C/EBP beta regulation of the tumor necrosis factor alpha gene. J Clin Invest. 1994 Oct;94(4):1449–1455. [PMC free article] [PubMed]
  • 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 alpha by transcriptional and post-transcriptional mechanisms. J Exp Med. 1990 Jul 1;172(1):151–158. [PMC free article] [PubMed]
  • Franza BR, Jr, Josephs SF, Gilman MZ, Ryan W, Clarkson B. Characterization of cellular proteins recognizing the HIV enhancer using a microscale DNA-affinity precipitation assay. Nature. 330(6146):391–395. [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]
  • Denis M, Ghadirian E. Interaction between Mycobacterium avium and human immunodeficiency virus type 1 (HIV-1) in bronchoalveolar macrophages of normal and HIV-1-infected subjects. Am J Respir Cell Mol Biol. 1994 Oct;11(4):487–495. [PubMed]
  • Brach MA, Hass R, Sherman ML, Gunji H, Weichselbaum R, Kufe D. Ionizing radiation induces expression and binding activity of the nuclear factor kappa B. J Clin Invest. 1991 Aug;88(2):691–695. [PMC free article] [PubMed]
  • Stanley SK, Folks TM, Fauci AS. Induction of expression of human immunodeficiency virus in a chronically infected promonocytic cell line by ultraviolet irradiation. AIDS Res Hum Retroviruses. 1989 Aug;5(4):375–384. [PubMed]
  • Desai-Yajnik V, Samuels HH. The NF-kappa B and Sp1 motifs of the human immunodeficiency virus type 1 long terminal repeat function as novel thyroid hormone response elements. Mol Cell Biol. 1993 Aug;13(8):5057–5069. [PMC free article] [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]
  • Lebargy F, Branellec A, Deforges L, Bignon J, Bernaudin JF. HIV-1 in human alveolar macrophages from infected patients is latent in vivo but replicates after in vitro stimulation. Am J Respir Cell Mol Biol. 1994 Jan;10(1):72–78. [PubMed]
  • Langhoff E, Kalland KH, Haseltine WA. Early molecular replication of human immunodeficiency virus type 1 in cultured-blood-derived T helper dendritic cells. J Clin Invest. 1993 Jun;91(6):2721–2726. [PMC free article] [PubMed]
  • Whalen C, Horsburgh CR, Hom D, Lahart C, Simberkoff M, Ellner J. Accelerated course of human immunodeficiency virus infection after tuberculosis. Am J Respir Crit Care Med. 1995 Jan;151(1):129–135. [PubMed]
  • Walker CM, Moody DJ, Stites DP, Levy JA. CD8+ lymphocytes can control HIV infection in vitro by suppressing virus replication. Science. 1986 Dec 19;234(4783):1563–1566. [PubMed]
  • Makonkawkeyoon S, Limson-Pobre RN, Moreira AL, Schauf V, Kaplan G. Thalidomide inhibits the replication of human immunodeficiency virus type 1. Proc Natl Acad Sci U S A. 1993 Jul 1;90(13):5974–5978. [PMC free article] [PubMed]

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