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. 2004 Mar;59(3):247–251. doi: 10.1136/thx.2003.013763

Impairment of ß chemokine and cytokine production in patients with HIV related Pneumocystis jerovici pneumonia

D Israel-Biet 1, H Esvant 1, A Laval 1, J Cadranel 1
PMCID: PMC1746968  PMID: 14985564

Abstract

Background: Pneumocystis jerovici pneumonia (PJP) remains a frequent opportunistic infection in HIV infected patients which markedly upregulates HIV replication by mechanisms so far poorly elucidated. PJP triggers the production of proinflammatory mediators with activating effects on HIV. However, anti-inflammatory factors with inhibiting effects on HIV are normally produced in parallel. We postulated that an imbalance of mediators normally controlling HIV replication could underlie its marked increase during PJP.

Methods: The production of tumour necrosis factor α (TNFα), interleukins IL-6 and IL-10, and ß-chemokine by bronchoalveolar lavage (BAL) cells recovered from HIV infected patients with and without PJP was compared. The pulmonary viral load was determined and correlations with cytokine and chemokine production were examined.

Results: TNFα and IL-6 release was similar in patients with and without PJP but IL-10 and ß-chemokine release was markedly lower in the PJP group (IL-10: p<10-2, RANTES, MIP-1α and MIP-1ß: p<0.001). The pulmonary viral load was markedly higher in patients with PJP (p<0.001) and correlated negatively with levels of MIP-1α, RANTES and IL-10 in BAL fluid cells (p<0.05).

Conclusion: Pulmonary IL-10 and ß-chemokine production is markedly defective in HIV infected patients with PJP, while pulmonary TNFα and IL-6 levels are normal. The resulting excess of these latter factors, which are known to upregulate HIV replication, might contribute to the increase in pulmonary viral load and to the more rapid HIV disease progression observed in patients with PJP.

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Selected References

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  1. Akridge R. E., Oyafuso L. K., Reed S. G. IL-10 is induced during HIV-1 infection and is capable of decreasing viral replication in human macrophages. J Immunol. 1994 Dec 15;153(12):5782–5789. [PubMed] [Google Scholar]
  2. Bakri Y., Amzazi S., Mannioui A., Benjouad A. The susceptibility of macrophages to human immunodeficiency virus type 1 X4 isolates depends on their activation state. Biomed Pharmacother. 2001 Feb;55(1):32–38. doi: 10.1016/s0753-3322(00)00015-9. [DOI] [PubMed] [Google Scholar]
  3. Benfield T. L., Lundgren B., Levine S. J., Kronborg G., Shelhamer J. H., Lundgren J. D. The major surface glycoprotein of Pneumocystis carinii induces release and gene expression of interleukin-8 and tumor necrosis factor alpha in monocytes. Infect Immun. 1997 Nov;65(11):4790–4794. doi: 10.1128/iai.65.11.4790-4794.1997. [DOI] [PMC free article] [PubMed] [Google Scholar]
  4. Capobianchi M. R., Abbate I., Antonelli G., Turriziani O., Dolei A., Dianzani F. Inhibition of HIV type 1 BaL replication by MIP-1alpha, MIP-1beta, and RANTES in macrophages. AIDS Res Hum Retroviruses. 1998 Feb 10;14(3):233–240. doi: 10.1089/aid.1998.14.233. [DOI] [PubMed] [Google Scholar]
  5. Denis M., Ghadirian E. Dysregulation of interleukin 8, interleukin 10, and interleukin 12 release by alveolar macrophages from HIV type 1-infected subjects. AIDS Res Hum Retroviruses. 1994 Dec;10(12):1619–1627. doi: 10.1089/aid.1994.10.1619. [DOI] [PubMed] [Google Scholar]
  6. Finnegan A., Roebuck K. A., Nakai B. E., Gu D. S., Rabbi M. F., Song S., Landay A. L. IL-10 cooperates with TNF-alpha to activate HIV-1 from latently and acutely infected cells of monocyte/macrophage lineage. J Immunol. 1996 Jan 15;156(2):841–851. [PubMed] [Google Scholar]
  7. Fraziano M., Cappelli G., Santucci M., Mariani F., Amicosante M., Casarini M., Giosue S., Bisetti A., Colizzi V. Expression of CCR5 is increased in human monocyte-derived macrophages and alveolar macrophages in the course of in vivo and in vitro Mycobacterium tuberculosis infection. AIDS Res Hum Retroviruses. 1999 Jul 1;15(10):869–874. doi: 10.1089/088922299310575. [DOI] [PubMed] [Google Scholar]
  8. Garrait V., Cadranel J., Esvant H., Herry I., Morinet P., Mayaud C., Israël-Biet D. Tuberculosis generates a microenvironment enhancing the productive infection of local lymphocytes by HIV. J Immunol. 1997 Sep 15;159(6):2824–2830. [PubMed] [Google Scholar]
  9. Goletti D., Weissman D., Jackson R. W., Collins F., Kinter A., Fauci A. S. The in vitro induction of human immunodeficiency virus (HIV) replication in purified protein derivative-positive HIV-infected persons by recall antigen response to Mycobacterium tuberculosis is the result of a balance of the effects of endogenous interleukin-2 and proinflammatory and antiinflammatory cytokines. J Infect Dis. 1998 May;177(5):1332–1338. doi: 10.1086/515276. [DOI] [PubMed] [Google Scholar]
  10. Hamilton T. A., Ohmori Y., Tebo J. M., Kishore R. Regulation of macrophage gene expression by pro- and anti-inflammatory cytokines. Pathobiology. 1999;67(5-6):241–244. doi: 10.1159/000028101. [DOI] [PubMed] [Google Scholar]
  11. Hoshino Yoshihiko, Nakata Koh, Hoshino Satomi, Honda Yoshihiro, Tse Doris B., Shioda Tatsuo, Rom William N., Weiden Michael. Maximal HIV-1 replication in alveolar macrophages during tuberculosis requires both lymphocyte contact and cytokines. J Exp Med. 2002 Feb 18;195(4):495–505. doi: 10.1084/jem.20011614. [DOI] [PMC free article] [PubMed] [Google Scholar]
  12. Israël-Biet D., Cadranel J., Beldjord K., Andrieu J. M., Jeffrey A., Even P. Tumor necrosis factor production in HIV-seropositive subjects. Relationship with lung opportunistic infections and HIV expression in alveolar macrophages. J Immunol. 1991 Jul 15;147(2):490–494. [PubMed] [Google Scholar]
  13. Israël-Biet D., Cadranel J., Even P. Human immunodeficiency virus production by alveolar lymphocytes is increased during Pneumocystis carinii pneumonia. Am Rev Respir Dis. 1993 Nov;148(5):1308–1312. doi: 10.1164/ajrccm/148.5.1308. [DOI] [PubMed] [Google Scholar]
  14. Kandil O., Fishman J. A., Koziel H., Pinkston P., Rose R. M., Remold H. G. Human immunodeficiency virus type 1 infection of human macrophages modulates the cytokine response to Pneumocystis carinii. Infect Immun. 1994 Feb;62(2):644–650. doi: 10.1128/iai.62.2.644-650.1994. [DOI] [PMC free article] [PubMed] [Google Scholar]
  15. Kinter A. L., Ostrowski M., Goletti D., Oliva A., Weissman D., Gantt K., Hardy E., Jackson R., Ehler L., Fauci A. S. HIV replication in CD4+ T cells of HIV-infected individuals is regulated by a balance between the viral suppressive effects of endogenous beta-chemokines and the viral inductive effects of other endogenous cytokines. Proc Natl Acad Sci U S A. 1996 Nov 26;93(24):14076–14081. doi: 10.1073/pnas.93.24.14076. [DOI] [PMC free article] [PubMed] [Google Scholar]
  16. Koziel H., Kim S., Reardon C., Li X., Garland R., Pinkston P., Kornfeld H. Enhanced in vivo human immunodeficiency virus-1 replication in the lungs of human immunodeficiency virus-infected persons with Pneumocystis carinii pneumonia. Am J Respir Crit Care Med. 1999 Dec;160(6):2048–2055. doi: 10.1164/ajrccm.160.6.9902099. [DOI] [PubMed] [Google Scholar]
  17. Lawn S. D., Roberts B. D., Griffin G. E., Folks T. M., Butera S. T. Cellular compartments of human immunodeficiency virus type 1 replication in vivo: determination by presence of virion-associated host proteins and impact of opportunistic infection. J Virol. 2000 Jan;74(1):139–145. [PMC free article] [PubMed] [Google Scholar]
  18. Lederman M. M., Georges D. L., Kusner D. J., Mudido P., Giam C. Z., Toossi Z. Mycobacterium tuberculosis and its purified protein derivative activate expression of the human immunodeficiency virus. J Acquir Immune Defic Syndr. 1994 Jul;7(7):727–733. [PubMed] [Google Scholar]
  19. Lu W., Israël-Biet D. Virion concentration in bronchoalveolar lavage fluids of HIV infected patients. Lancet. 1993 Jul 31;342(8866):298–298. doi: 10.1016/0140-6736(93)91839-e. [DOI] [PubMed] [Google Scholar]
  20. Mayanja-Kizza H., Wajja A., Wu M., Peters P., Nalugwa G., Mubiru F., Aung H., Vanham G., Hirsch C., Whalen C. Activation of beta-chemokines and CCR5 in persons infected with human immunodeficiency virus type 1 and tuberculosis. J Infect Dis. 2001 May 17;183(12):1801–1804. doi: 10.1086/320724. [DOI] [PubMed] [Google Scholar]
  21. Moore K. W., de Waal Malefyt R., Coffman R. L., O'Garra A. Interleukin-10 and the interleukin-10 receptor. Annu Rev Immunol. 2001;19:683–765. doi: 10.1146/annurev.immunol.19.1.683. [DOI] [PubMed] [Google Scholar]
  22. Nakata K., Rom W. N., Honda Y., Condos R., Kanegasaki S., Cao Y., Weiden M. Mycobacterium tuberculosis enhances human immunodeficiency virus-1 replication in the lung. Am J Respir Crit Care Med. 1997 Mar;155(3):996–1003. doi: 10.1164/ajrccm.155.3.9117038. [DOI] [PubMed] [Google Scholar]
  23. Orenstein J. M., Fox C., Wahl S. M. Macrophages as a source of HIV during opportunistic infections. Science. 1997 Jun 20;276(5320):1857–1861. doi: 10.1126/science.276.5320.1857. [DOI] [PubMed] [Google Scholar]
  24. Ostrowski M. A., Gu J. X., Kovacs C., Freedman J., Luscher M. A., 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-gamma and interleukin-10 responses. J Infect Dis. 2001 Oct 15;184(10):1268–1278. doi: 10.1086/324005. [DOI] [PubMed] [Google Scholar]
  25. Perenboom R. M., Sauerwein R. W., Beckers P., van Schijndel A. C., van Steenwijk R. P., Borleffs J. C., van Leusen R., van der Meer J. W. Cytokine profiles in bronchoalveolar lavage fluid and blood in HIV-seropositive patients with Pneumocystis carinii pneumonia. Eur J Clin Invest. 1997 Apr;27(4):333–339. doi: 10.1046/j.1365-2362.1997.1170661.x. [DOI] [PubMed] [Google Scholar]
  26. Poli G., Bressler P., Kinter A., Duh E., Timmer W. C., Rabson A., Justement J. S., Stanley S., Fauci A. S. 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. doi: 10.1084/jem.172.1.151. [DOI] [PMC free article] [PubMed] [Google Scholar]
  27. Poli G., Kinter A., Justement J. S., Kehrl J. H., Bressler P., Stanley S., Fauci A. S. 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. doi: 10.1073/pnas.87.2.782. [DOI] [PMC free article] [PubMed] [Google Scholar]
  28. Rabbi M. F., Finnegan A., Al-Harthi L., Song S., Roebuck K. A. Interleukin-10 enhances tumor necrosis factor-alpha activation of HIV-1 transcription in latently infected T cells. J Acquir Immune Defic Syndr Hum Retrovirol. 1998 Dec 1;19(4):321–331. doi: 10.1097/00042560-199812010-00002. [DOI] [PubMed] [Google Scholar]
  29. Ruan Sanbao, Tate Chandra, Lee Janet J., Ritter Thomas, Kolls Jay K., Shellito Judd E. Local delivery of the viral interleukin-10 gene suppresses tissue inflammation in murine Pneumocystis carinii infection. Infect Immun. 2002 Nov;70(11):6107–6113. doi: 10.1128/IAI.70.11.6107-6113.2002. [DOI] [PMC free article] [PubMed] [Google Scholar]
  30. Shalekoff S., Pendle S., Johnson D., Martin D. J., Tiemessen C. T. Distribution of the human immunodeficiency virus coreceptors CXCR4 and CCR5 on leukocytes of persons with human immunodeficiency virus type 1 infection and pulmonary tuberculosis: implications for pathogenesis. J Clin Immunol. 2001 Nov;21(6):390–401. doi: 10.1023/a:1013121625962. [DOI] [PubMed] [Google Scholar]
  31. Shaunak S., Veryard C., Javan C. Severe Pneumocystis carinii pneumonia increases the infectious titre of HIV-1 in blood and can promote the expansion of viral chemokine co-receptor tropism. J Infect. 2001 Jul;43(1):3–6. doi: 10.1053/jinf.2001.0885. [DOI] [PubMed] [Google Scholar]
  32. Shin H. D., Winkler C., Stephens J. C., Bream J., Young H., Goedert J. J., O'Brien T. R., Vlahov D., Buchbinder S., Giorgi J. Genetic restriction of HIV-1 pathogenesis to AIDS by promoter alleles of IL10. Proc Natl Acad Sci U S A. 2000 Dec 19;97(26):14467–14472. doi: 10.1073/pnas.97.26.14467. [DOI] [PMC free article] [PubMed] [Google Scholar]
  33. Stylianou E., Aukrust P., Kvale D., Müller F., Frøland S. S. IL-10 in HIV infection: increasing serum IL-10 levels with disease progression--down-regulatory effect of potent anti-retroviral therapy. Clin Exp Immunol. 1999 Apr;116(1):115–120. doi: 10.1046/j.1365-2249.1999.00865.x. [DOI] [PMC free article] [PubMed] [Google Scholar]
  34. Tadmori W., Mondal D., Tadmori I., Prakash O. Transactivation of human immunodeficiency virus type 1 long terminal repeats by cell surface tumor necrosis factor alpha. J Virol. 1991 Dec;65(12):6425–6429. doi: 10.1128/jvi.65.12.6425-6429.1991. [DOI] [PMC free article] [PubMed] [Google Scholar]
  35. Tartakovsky B., Turner D., Vardinon N., Burke M., Yust I. Increased intracellular accumulation of macrophage inflammatory protein 1beta and its decreased secretion correlate with advanced HIV disease. J Acquir Immune Defic Syndr Hum Retrovirol. 1999 Apr 15;20(5):420–422. doi: 10.1097/00042560-199904150-00002. [DOI] [PubMed] [Google Scholar]
  36. Toossi Z., Johnson J. L., Kanost R. A., Wu M., Luzze H., Peters P., Okwera A., Joloba M., Mugyenyi P., Mugerwa R. D. Increased replication of HIV-1 at sites of Mycobacterium tuberculosis infection: potential mechanisms of viral activation. J Acquir Immune Defic Syndr. 2001 Sep 1;28(1):1–8. doi: 10.1097/00042560-200109010-00001. [DOI] [PubMed] [Google Scholar]
  37. Toossi Z., Mayanja-Kizza H., Hirsch C. S., Edmonds K. L., Spahlinger T., Hom D. L., Aung H., Mugyenyi P., Ellner J. J., Whalen C. W. Impact of tuberculosis (TB) on HIV-1 activity in dually infected patients. Clin Exp Immunol. 2001 Feb;123(2):233–238. doi: 10.1046/j.1365-2249.2001.01401.x. [DOI] [PMC free article] [PubMed] [Google Scholar]
  38. Ullum H., Cozzi Lepri A., Victor J., Aladdin H., Phillips A. N., Gerstoft J., Skinhøj P., Pedersen B. K. Production of beta-chemokines in human immunodeficiency virus (HIV) infection: evidence that high levels of macrophage inflammatory protein-1beta are associated with a decreased risk of HIV disease progression. J Infect Dis. 1998 Feb;177(2):331–336. doi: 10.1086/514192. [DOI] [PubMed] [Google Scholar]
  39. Vassallo R., Standing J. E., Limper A. H. Isolated Pneumocystis carinii cell wall glucan provokes lower respiratory tract inflammatory responses. J Immunol. 2000 Apr 1;164(7):3755–3763. doi: 10.4049/jimmunol.164.7.3755. [DOI] [PubMed] [Google Scholar]
  40. Verani A., Scarlatti G., Comar M., Tresoldi E., Polo S., Giacca M., Lusso P., Siccardi A. G., Vercelli D. C-C chemokines released by lipopolysaccharide (LPS)-stimulated human macrophages suppress HIV-1 infection in both macrophages and T cells. J Exp Med. 1997 Mar 3;185(5):805–816. doi: 10.1084/jem.185.5.805. [DOI] [PMC free article] [PubMed] [Google Scholar]
  41. Vicenzi E., Alfano M., Ghezzi S., Gatti A., Veglia F., Lazzarin A., Sozzani S., Mantovani A., Poli G. Divergent regulation of HIV-1 replication in PBMC of infected individuals by CC chemokines: suppression by RANTES, MIP-1alpha, and MCP-3, and enhancement by MCP-1. J Leukoc Biol. 2000 Sep;68(3):405–412. [PubMed] [Google Scholar]
  42. Wahl S. M., Greenwell-Wild T., Hale-Donze H., Moutsopoulos N., Orenstein J. M. Permissive factors for HIV-1 infection of macrophages. J Leukoc Biol. 2000 Sep;68(3):303–310. [PubMed] [Google Scholar]
  43. Wahl S. M., Greenwell-Wild T., Peng G., Hale-Donze H., Orenstein J. M. Co-infection with opportunistic pathogens promotes human immunodeficiency virus type 1 infection in macrophages. J Infect Dis. 1999 May;179 (Suppl 3):S457–S460. doi: 10.1086/314814. [DOI] [PubMed] [Google Scholar]
  44. Weissman D., Poli G., Fauci A. S. IL-10 synergizes with multiple cytokines in enhancing HIV production in cells of monocytic lineage. J Acquir Immune Defic Syndr Hum Retrovirol. 1995 Aug 15;9(5):442–449. [PubMed] [Google Scholar]
  45. Worgall S., Connor R., Kaner R. J., Fenamore E., Sheridan K., Singh R., Crystal R. G. Expression and use of human immunodeficiency virus type 1 coreceptors by human alveolar macrophages. J Virol. 1999 Jul;73(7):5865–5874. doi: 10.1128/jvi.73.7.5865-5874.1999. [DOI] [PMC free article] [PubMed] [Google Scholar]
  46. Wright T. W., Johnston C. J., Harmsen A. G., Finkelstein J. N. Chemokine gene expression during Pneumocystis carinii-driven pulmonary inflammation. Infect Immun. 1999 Jul;67(7):3452–3460. doi: 10.1128/iai.67.7.3452-3460.1999. [DOI] [PMC free article] [PubMed] [Google Scholar]
  47. Zhang Y., Nakata K., Weiden M., Rom W. N. Mycobacterium tuberculosis enhances human immunodeficiency virus-1 replication by transcriptional activation at the long terminal repeat. J Clin Invest. 1995 May;95(5):2324–2331. doi: 10.1172/JCI117924. [DOI] [PMC free article] [PubMed] [Google Scholar]

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