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. 1997 May;71(5):3628–3635. doi: 10.1128/jvi.71.5.3628-3635.1997

Inflammatory cytokine expression is correlated with the level of human immunodeficiency virus (HIV) transcripts in HIV-infected placental trophoblastic cells.

B N Lee 1, N Ordonez 1, E J Popek 1, J G Lu 1, A Helfgott 1, N Eriksen 1, H Hammill 1, C Kozinetz 1, M Doyle 1, M Kline 1, C Langston 1, W T Shearer 1, J M Reuben 1
PMCID: PMC191511  PMID: 9094636

Abstract

The inflammatory cytokines interleukin-1beta (IL-1beta), IL-6, and tumor necrosis factor alpha (TNF-alpha) have been associated with increased human immunodeficiency virus (HIV) expression and enhanced lymphocyte adhesion to trophoblastic cells in experimental systems. To determine if there is a correlation between the expression of these cytokines and the levels of HIV transcripts in trophoblasts of term placentas from HIV-infected women, we studied the placentae of 30 HIV-positive and 13 control gravidae. Twenty-three of the HIV-positive women received zidovudine (ZDV) as prophylaxis against HIV vertical transmission; only one of the seven women who did not receive ZDV was a transmitter, for an overall vertical transmission rate of 3.8%. Cytokine production was measured by enzyme-linked immunosorbent assay in the supernatants of trophoblastic cell cultures. Additionally, cytokine transcripts and HIV gag sequences were determined by a quantitative reverse transcription-PCR assay. In general, trophoblastic cells of HIV-positive placentas expressed significantly higher levels of IL-1beta, IL-6, and TNF-alpha than those of control placentas. All placentas from HIV-positive women expressed HIV gag transcripts at either a low (<156 copies per microg of total RNA) or a high (>156 copies per microg of total RNA) level. There was a statistically significant positive association between the basal level of TNF-alpha production and the level of HIV gag transcripts of HIV-positive placental trophoblastic cells. Nevertheless, these data, coupled with a low transmission rate, would indicate that some other factors, perhaps working in concert with cytokines, are necessary for vertical transmission of HIV from mother to infant.

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Selected References

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  1. Ahmad N. Maternal-Fetal Transmission of Human Immunodeficiency Virus. J Biomed Sci. 1996 Jul-Aug;3(4):238–250. doi: 10.1007/BF02253703. [DOI] [PubMed] [Google Scholar]
  2. Bourinbaiar A. S., Krasinski K., Borkowsky W., Lee-Huang S. Protective effect of interferon-alpha against cell-mediated human immunodeficiency virus transmission resulting from coculture of infected lymphocytes with fetal trophoblasts. J Interferon Cytokine Res. 1995 Jun;15(6):503–508. doi: 10.1089/jir.1995.15.503. [DOI] [PubMed] [Google Scholar]
  3. Chomczynski P., Sacchi N. Single-step method of RNA isolation by acid guanidinium thiocyanate-phenol-chloroform extraction. Anal Biochem. 1987 Apr;162(1):156–159. doi: 10.1006/abio.1987.9999. [DOI] [PubMed] [Google Scholar]
  4. Chou Q., Russell M., Birch D. E., Raymond J., Bloch W. Prevention of pre-PCR mis-priming and primer dimerization improves low-copy-number amplifications. Nucleic Acids Res. 1992 Apr 11;20(7):1717–1723. doi: 10.1093/nar/20.7.1717. [DOI] [PMC free article] [PubMed] [Google Scholar]
  5. Coccia E. M., Krust B., Hovanessian A. G. Specific inhibition of viral protein synthesis in HIV-infected cells in response to interferon treatment. J Biol Chem. 1994 Sep 16;269(37):23087–23094. [PubMed] [Google Scholar]
  6. Connor E. M., Sperling R. S., Gelber R., Kiselev P., Scott G., O'Sullivan M. J., VanDyke R., Bey M., Shearer W., Jacobson R. L. Reduction of maternal-infant transmission of human immunodeficiency virus type 1 with zidovudine treatment. Pediatric AIDS Clinical Trials Group Protocol 076 Study Group. N Engl J Med. 1994 Nov 3;331(18):1173–1180. doi: 10.1056/NEJM199411033311801. [DOI] [PubMed] [Google Scholar]
  7. Corrales I., Weersink A. J., Verhoef J., van Kessel K. P. Serum-independent binding of lipopolysaccharide to human monocytes is trypsin sensitive and does not involve CD14. Immunology. 1993 Sep;80(1):84–89. [PMC free article] [PubMed] [Google Scholar]
  8. Douglas G. C., Fry G. N., Thirkill T., Holmes E., Hakim H., Jennings M., King B. F. Cell-mediated infection of human placental trophoblast with HIV in vitro. AIDS Res Hum Retroviruses. 1991 Sep;7(9):735–740. doi: 10.1089/aid.1991.7.735. [DOI] [PubMed] [Google Scholar]
  9. Douglas G. C., Hu J., Thirkill T. L., Hovanes K., Sharma S., King B. F. Effect of cytokines and anti-adhesion molecule antibodies on the adhesion of lymphocytic cells to human syncytiotrophoblast. J Reprod Immunol. 1994 Aug;27(1):49–62. doi: 10.1016/0165-0378(94)90014-0. [DOI] [PubMed] [Google Scholar]
  10. Douglas G. C., King B. F. Isolation of pure villous cytotrophoblast from term human placenta using immunomagnetic microspheres. J Immunol Methods. 1989 May 12;119(2):259–268. doi: 10.1016/0022-1759(89)90405-5. [DOI] [PubMed] [Google Scholar]
  11. Ebbesen P., Hager H., Nørskov-Lauritsen N., Aboagye-Mathiesen G., Zdravkovic M., Villadsen J., Liu X., Petersen P. M., Bambra C., Nyongo A. Concurrence of high levels of interferons alpha and beta in cord and maternal blood and simultaneous presence of interferon in trophoblast in an African population. J Interferon Cytokine Res. 1995 Feb;15(2):123–128. doi: 10.1089/jir.1995.15.123. [DOI] [PubMed] [Google Scholar]
  12. Folks T. M., Justement J., Kinter A., Dinarello C. A., Fauci A. S. Cytokine-induced expression of HIV-1 in a chronically infected promonocyte cell line. Science. 1987 Nov 6;238(4828):800–802. doi: 10.1126/science.3313729. [DOI] [PubMed] [Google Scholar]
  13. Garcia-Lloret M. I., Yui J., Winkler-Lowen B., Guilbert L. J. Epidermal growth factor inhibits cytokine-induced apoptosis of primary human trophoblasts. J Cell Physiol. 1996 May;167(2):324–332. doi: 10.1002/(SICI)1097-4652(199605)167:2<324::AID-JCP17>3.0.CO;2-7. [DOI] [PubMed] [Google Scholar]
  14. Gessani S., Testa U., Varano B., Di Marzio P., Borghi P., Conti L., Barberi T., Tritarelli E., Martucci R., Seripa D. Enhanced production of LPS-induced cytokines during differentiation of human monocytes to macrophages. Role of LPS receptors. J Immunol. 1993 Oct 1;151(7):3758–3766. [PubMed] [Google Scholar]
  15. Guilbert L., Robertson S. A., Wegmann T. G. The trophoblast as an integral component of a macrophage-cytokine network. Immunol Cell Biol. 1993 Feb;71(Pt 1):49–57. doi: 10.1038/icb.1993.5. [DOI] [PubMed] [Google Scholar]
  16. Howatson A. G., Farquharson M., Meager A., McNicol A. M., Foulis A. K. Localization of alpha-interferon in the human feto-placental unit. J Endocrinol. 1988 Dec;119(3):531–534. doi: 10.1677/joe.0.1190531. [DOI] [PubMed] [Google Scholar]
  17. Hsu S. M., Raine L., Fanger H. Use of avidin-biotin-peroxidase complex (ABC) in immunoperoxidase techniques: a comparison between ABC and unlabeled antibody (PAP) procedures. J Histochem Cytochem. 1981 Apr;29(4):577–580. doi: 10.1177/29.4.6166661. [DOI] [PubMed] [Google Scholar]
  18. Kameda T., Matsuzaki N., Sawai K., Okada T., Saji F., Matsuda T., Hirano T., Kishimoto T., Tanizawa O. Production of interleukin-6 by normal human trophoblast. Placenta. 1990 May-Jun;11(3):205–213. doi: 10.1016/s0143-4004(05)80266-8. [DOI] [PubMed] [Google Scholar]
  19. Kassen A., Sutkowski D. M., Ahn H., Sensibar J. A., Kozlowski J. M., Lee C. Stromal cells of the human prostate: initial isolation and characterization. Prostate. 1996 Feb;28(2):89–97. doi: 10.1002/(SICI)1097-0045(199602)28:2<89::AID-PROS3>3.0.CO;2-I. [DOI] [PubMed] [Google Scholar]
  20. Kauma S. W., Walsh S. W., Nestler J. E., Turner T. T. Interleukin-1 is induced in the human placenta by endotoxin and isolation procedures for trophoblasts. J Clin Endocrinol Metab. 1992 Sep;75(3):951–955. doi: 10.1210/jcem.75.3.1517391. [DOI] [PubMed] [Google Scholar]
  21. Kliman H. J., Nestler J. E., Sermasi E., Sanger J. M., Strauss J. F., 3rd Purification, characterization, and in vitro differentiation of cytotrophoblasts from human term placentae. Endocrinology. 1986 Apr;118(4):1567–1582. doi: 10.1210/endo-118-4-1567. [DOI] [PubMed] [Google Scholar]
  22. Laure F., Courgnaud V., Rouzioux C., Blanche S., Veber F., Burgard M., Jacomet C., Griscelli C., Brechot C. Detection of HIV1 DNA in infants and children by means of the polymerase chain reaction. Lancet. 1988 Sep 3;2(8610):538–541. doi: 10.1016/s0140-6736(88)92659-1. [DOI] [PubMed] [Google Scholar]
  23. Lewis S. H., Reynolds-Kohler C., Fox H. E., Nelson J. A. HIV-1 in trophoblastic and villous Hofbauer cells, and haematological precursors in eight-week fetuses. Lancet. 1990 Mar 10;335(8689):565–568. doi: 10.1016/0140-6736(90)90349-a. [DOI] [PubMed] [Google Scholar]
  24. Li Y., Matsuzaki N., Masuhiro K., Kameda T., Taniguchi T., Saji F., Yone K., Tanizawa O. Trophoblast-derived tumor necrosis factor-alpha induces release of human chorionic gonadotropin using interleukin-6 (IL-6) and IL-6-receptor-dependent system in the normal human trophoblasts. J Clin Endocrinol Metab. 1992 Jan;74(1):184–191. doi: 10.1210/jcem.74.1.1727819. [DOI] [PubMed] [Google Scholar]
  25. Librach C. L., Feigenbaum S. L., Bass K. E., Cui T. Y., Verastas N., Sadovsky Y., Quigley J. P., French D. L., Fisher S. J. Interleukin-1 beta regulates human cytotrophoblast metalloproteinase activity and invasion in vitro. J Biol Chem. 1994 Jun 24;269(25):17125–17131. [PubMed] [Google Scholar]
  26. Maury W., Potts B. J., Rabson A. B. HIV-1 infection of first-trimester and term human placental tissue: a possible mode of maternal-fetal transmission. J Infect Dis. 1989 Oct;160(4):583–588. doi: 10.1093/infdis/160.4.583. [DOI] [PubMed] [Google Scholar]
  27. McGann K. A., Collman R., Kolson D. L., Gonzalez-Scarano F., Coukos G., Coutifaris C., Strauss J. F., Nathanson N. Human immunodeficiency virus type 1 causes productive infection of macrophages in primary placental cell cultures. J Infect Dis. 1994 Apr;169(4):746–753. doi: 10.1093/infdis/169.4.746. [DOI] [PubMed] [Google Scholar]
  28. Mundy D. C., Schinazi R. F., Gerber A. R., Nahmias A. J., Randall H. W., Jr Human immunodeficiency virus isolated from amniotic fluid. Lancet. 1987 Aug 22;2(8556):459–460. doi: 10.1016/s0140-6736(87)91001-4. [DOI] [PubMed] [Google Scholar]
  29. 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. doi: 10.1038/326711a0. [DOI] [PubMed] [Google Scholar]
  30. Osborn L., Kunkel S., Nabel G. J. 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. doi: 10.1073/pnas.86.7.2336. [DOI] [PMC free article] [PubMed] [Google Scholar]
  31. Poli G., Fauci A. S. The effect of cytokines and pharmacologic agents on chronic HIV infection. AIDS Res Hum Retroviruses. 1992 Feb;8(2):191–197. doi: 10.1089/aid.1992.8.191. [DOI] [PubMed] [Google Scholar]
  32. Poli G., Kinter A. L., Fauci A. S. Interleukin 1 induces expression of the human immunodeficiency virus alone and in synergy with interleukin 6 in chronically infected U1 cells: inhibition of inductive effects by the interleukin 1 receptor antagonist. Proc Natl Acad Sci U S A. 1994 Jan 4;91(1):108–112. doi: 10.1073/pnas.91.1.108. [DOI] [PMC free article] [PubMed] [Google Scholar]
  33. Reuben J. M., Gonik B., Li S., Loo L., Turpin J. Induction of cytokines in normal placental cells by the human immunodeficiency virus. Lymphokine Cytokine Res. 1991 Jun;10(3):195–199. [PubMed] [Google Scholar]
  34. Reuben J. M., Turpin J. A., Lee B. N., Doyle M., Gonik B., Jacobson R., Shearer W. T. Induction of inflammatory cytokines in placental monocytes of gravidae infected with the human immunodeficiency virus type 1. J Interferon Cytokine Res. 1996 Nov;16(11):963–971. doi: 10.1089/jir.1996.16.963. [DOI] [PubMed] [Google Scholar]
  35. Rogers M. F., Ou C. Y., Rayfield M., Thomas P. A., Schoenbaum E. E., Abrams E., Krasinski K., Selwyn P. A., Moore J., Kaul A. Use of the polymerase chain reaction for early detection of the proviral sequences of human immunodeficiency virus in infants born to seropositive mothers. New York City Collaborative Study of Maternal HIV Transmission and Montefiore Medical Center HIV Perinatal Transmission Study Group. N Engl J Med. 1989 Jun 22;320(25):1649–1654. doi: 10.1056/NEJM198906223202503. [DOI] [PubMed] [Google Scholar]
  36. Schnittman S. M., Singer K. H., Greenhouse J. J., Stanley S. K., Whichard L. P., Le P. T., Haynes B. F., Fauci A. S. Thymic microenvironment induces HIV expression. Physiologic secretion of IL-6 by thymic epithelial cells up-regulates virus expression in chronically infected cells. J Immunol. 1991 Oct 15;147(8):2553–2558. [PubMed] [Google Scholar]
  37. Schwartz D. A., Nahmias A. J. Human immunodeficiency virus and the placenta. Current concepts of vertical transmission in relation to other viral agents. Ann Clin Lab Sci. 1991 Jul-Aug;21(4):264–274. [PubMed] [Google Scholar]
  38. Schwartz D. H., Sharma U. K., Perlman E. J., Blakemore K. Adherence of human immunodeficiency virus-infected lymphocytes to fetal placental cells: a model of maternal --> fetal transmission. Proc Natl Acad Sci U S A. 1995 Feb 14;92(4):978–982. doi: 10.1073/pnas.92.4.978. [DOI] [PMC free article] [PubMed] [Google Scholar]
  39. Shalaby M. R., Aggarwal B. B., Rinderknecht E., Svedersky L. P., Finkle B. S., Palladino M. A., Jr Activation of human polymorphonuclear neutrophil functions by interferon-gamma and tumor necrosis factors. J Immunol. 1985 Sep;135(3):2069–2073. [PubMed] [Google Scholar]
  40. St Louis M. E., Kamenga M., Brown C., Nelson A. M., Manzila T., Batter V., Behets F., Kabagabo U., Ryder R. W., Oxtoby M. Risk for perinatal HIV-1 transmission according to maternal immunologic, virologic, and placental factors. JAMA. 1993 Jun 9;269(22):2853–2859. [PubMed] [Google Scholar]
  41. Taniguchi T., Matsuzaki N., Kameda T., Shimoya K., Jo T., Saji F., Tanizawa O. The enhanced production of placental interleukin-1 during labor and intrauterine infection. Am J Obstet Gynecol. 1991 Jul;165(1):131–137. doi: 10.1016/0002-9378(91)90241-i. [DOI] [PubMed] [Google Scholar]
  42. Thiry L., Sprecher-Goldberger S., Jonckheer T., Levy J., Van de Perre P., Henrivaux P., Cogniaux-LeClerc J., Clumeck N. Isolation of AIDS virus from cell-free breast milk of three healthy virus carriers. Lancet. 1985 Oct 19;2(8460):891–892. doi: 10.1016/s0140-6736(85)90156-4. [DOI] [PubMed] [Google Scholar]
  43. Walther Z., May L. T., Sehgal P. B. Transcriptional regulation of the interferon-beta 2/B cell differentiation factor BSF-2/hepatocyte-stimulating factor gene in human fibroblasts by other cytokines. J Immunol. 1988 Feb 1;140(3):974–977. [PubMed] [Google Scholar]
  44. Wofsy C. B., Cohen J. B., Hauer L. B., Padian N. S., Michaelis B. A., Evans L. A., Levy J. A. Isolation of AIDS-associated retrovirus from genital secretions of women with antibodies to the virus. Lancet. 1986 Mar 8;1(8480):527–529. doi: 10.1016/s0140-6736(86)90885-8. [DOI] [PubMed] [Google Scholar]
  45. Wright S. D., Ramos R. A., Tobias P. S., Ulevitch R. J., Mathison J. C. CD14, a receptor for complexes of lipopolysaccharide (LPS) and LPS binding protein. Science. 1990 Sep 21;249(4975):1431–1433. doi: 10.1126/science.1698311. [DOI] [PubMed] [Google Scholar]
  46. Yui J., Garcia-Lloret M., Wegmann T. G., Guilbert L. J. Cytotoxicity of tumour necrosis factor-alpha and gamma-interferon against primary human placental trophoblasts. Placenta. 1994 Dec;15(8):819–835. doi: 10.1016/s0143-4004(05)80184-5. [DOI] [PubMed] [Google Scholar]
  47. Zachar V., Ebbesen P., Thomas R. A., Zacharova V., Goustin A. S. Basal and Tat-transactivated expression from the human immunodeficiency virus type 1 long terminal repeat in human placental trophoblast rules out promoter-enhancer activation as the partial block to viral replication. J Gen Virol. 1994 Jun;75(Pt 6):1461–1468. doi: 10.1099/0022-1317-75-6-1461. [DOI] [PubMed] [Google Scholar]
  48. Zhang G. Y., Beltchev B., Fournier A., Zhang Y. H., Malassiné A., Bisbal C., Ehresmann B., Ehresmann C., Darlix J. L., Thang M. N. High levels of 2',5'-oligoadenylate synthetase and 2',5'-oligoadenylate-dependent endonuclease in human trophoblast. AIDS Res Hum Retroviruses. 1993 Feb;9(2):189–196. doi: 10.1089/aid.1993.9.189. [DOI] [PubMed] [Google Scholar]

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