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. 1995 Apr 1;181(4):1493–1505.

Neutrophils from human immunodeficiency virus (HIV)-seronegative donors induce HIV replication from HIV-infected patients' mononuclear cells and cell lines: an in vitro model of HIV transmission facilitated by Chlamydia trachomatis

PMCID: PMC2191973  PMID: 7699332

Abstract

Infection with a sexually transmitted disease (STD) increases the risk for human immunodeficiency virus (HIV) infection. Polymorphonuclear leukocytes (PMNs) are recruited into the genital tract by STD pathogens, such as Chlamydia trachomatis. Semen of HIV-infected men contains HIV associated with mononuclear cells. This study investigated the interaction among PMNs from HIV-uninfected persons, C. trachomatis, and HIV-infected cells and examined the mechanisms for enhanced HIV replication. We demonstrated that PMNs from HIV-seronegative donors induced HIV replication in mononuclear cells from 17 HIV-infected patients in medium without exogenous IL-2. HIV in the cell-free supernatants from cocultures of PMNs and patients' peripheral blood mononuclear cells (PBMCs) was replication competent, as indicated by their capacity to propagate HIV in a second round of culture using PBMCs from HIV-seronegative individuals and by the fact that proviral DNA was found in these cells. PMNs from HIV-seronegative donors increased HIV replication over 100-fold in chronically HIV-infected cell lines of the monocytic, T, and B cell lineages. Moreover, PMNs increased U1 cells' production of p24 antigen by as much as ninefold when compared with U1 cells cocultured with PBMCs. The addition of C. trachomatis to PMN and U1 coculture increased HIV replication by an additional ninefold at 24 h, whereas C. trachomatis alone had no effect on p24 antigen production by U1 cells. Thus, C. trachomatis serves not only to recruit PMNs, but also to interact with PMNs to increase HIV replication. HIV replication is triggered by contact of HIV-infected cells with PMNs, by the generation of reactive oxygen intermediates (ROIs), and by soluble factors such as TNF-alpha and IL-6. This is based on the findings that production of p24 antigen, IL-6, and TNF- alpha induced by PMNs is abrogated by disrupting or partitioning PMNs from HIV-infected cells; is inhibited by superoxide dismutase and catalase, enzymes that destroy ROIs; is enhanced by differentiated HL60 cells capable of producing ROIs; and is induced by PMNs tested negative for CMV. Furthermore, the production of ROIs is independent of HIV infection of mononuclear cells, since PMNs cocultured with HIV- uninfected parental monocytic and T cell lines generated ROIs. Therefore, the increased risk for acquiring HIV infection associated with chlamydia cervicitis may be related to the local recruitment of PMNs by C. trachomatis and the induction of infectious virus from mononuclear cells present in semen. These observations provide a rationale for strategies to reduce HIV transmission by control of STD.

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Selected References

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  1. Akrigg A., Wilkinson G. W., Oram J. D. The structure of the major immediate early gene of human cytomegalovirus strain AD169. Virus Res. 1985 Mar;2(2):107–121. doi: 10.1016/0168-1702(85)90242-4. [DOI] [PubMed] [Google Scholar]
  2. Ashida E. R., Scofield V. L. Lymphocyte major histocompatibility complex-encoded class II structures may act as sperm receptors. Proc Natl Acad Sci U S A. 1987 May;84(10):3395–3399. doi: 10.1073/pnas.84.10.3395. [DOI] [PMC free article] [PubMed] [Google Scholar]
  3. Bagasra O., Freund M., Weidmann J., Harley G. Interaction of human immunodeficiency virus with human sperm in vitro. J Acquir Immune Defic Syndr. 1988;1(5):431–435. [PubMed] [Google Scholar]
  4. Bird K. D. The use of spermicide containing nonoxynol-9 in the prevention of HIV infection. AIDS. 1991 Jul;5(7):791–796. doi: 10.1097/00002030-199107000-00001. [DOI] [PubMed] [Google Scholar]
  5. Bylund D. J., Ziegner U. H., Hooper D. G. Review of testing for human immunodeficiency virus. Clin Lab Med. 1992 Jun;12(2):305–333. [PubMed] [Google Scholar]
  6. Böyum A. Isolation of mononuclear cells and granulocytes from human blood. Isolation of monuclear cells by one centrifugation, and of granulocytes by combining centrifugation and sedimentation at 1 g. Scand J Clin Lab Invest Suppl. 1968;97:77–89. [PubMed] [Google Scholar]
  7. Caldwell H. D., Kromhout J., Schachter J. Purification and partial characterization of the major outer membrane protein of Chlamydia trachomatis. Infect Immun. 1981 Mar;31(3):1161–1176. doi: 10.1128/iai.31.3.1161-1176.1981. [DOI] [PMC free article] [PubMed] [Google Scholar]
  8. Cates W., Jr, Stewart F. H., Trussell J. Commentary: the quest for women's prophylactic methods--hopes vs science. Am J Public Health. 1992 Nov;82(11):1479–1482. doi: 10.2105/ajph.82.11.1479. [DOI] [PMC free article] [PubMed] [Google Scholar]
  9. Cates W., Jr, Stone K. M. Family planning, sexually transmitted diseases and contraceptive choice: a literature update--Part I. Fam Plann Perspect. 1992 Mar-Apr;24(2):75–84. [PubMed] [Google Scholar]
  10. Chvapil M., Droegemueller W., Owen J. A., Eskelson C. D., Betts K. Studies of nonoxynol-9. I. The effect on the vaginas of rabbits and rats. Fertil Steril. 1980 Apr;33(4):445–450. [PubMed] [Google Scholar]
  11. Clouse K. A., Powell D., Washington I., Poli G., Strebel K., Farrar W., Barstad P., Kovacs J., Fauci A. S., Folks T. M. 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] [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. Folks T. M., Justement J., Kinter A., Schnittman S., Orenstein J., Poli G., Fauci A. S. Characterization of a promonocyte clone chronically infected with HIV and inducible by 13-phorbol-12-myristate acetate. J Immunol. 1988 Feb 15;140(4):1117–1122. [PubMed] [Google Scholar]
  14. Folks T. M., Powell D., Lightfoote M., Koenig S., Fauci A. S., Benn S., Rabson A., Daugherty D., Gendelman H. E., Hoggan M. D. 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. doi: 10.1084/jem.164.1.280. [DOI] [PMC free article] [PubMed] [Google Scholar]
  15. Gerna G., Parea M., Percivalle E., Zipeto D., Silini E., Barbarini G., Milanesi G. Human cytomegalovirus viraemia in HIV-1-seropositive patients at various clinical stages of infection. AIDS. 1990 Oct;4(10):1027–1031. doi: 10.1097/00002030-199010000-00014. [DOI] [PubMed] [Google Scholar]
  16. Gerna G., Zipeto D., Percivalle E., Parea M., Revello M. G., Maccario R., Peri G., Milanesi G. Human cytomegalovirus infection of the major leukocyte subpopulations and evidence for initial viral replication in polymorphonuclear leukocytes from viremic patients. J Infect Dis. 1992 Dec;166(6):1236–1244. doi: 10.1093/infdis/166.6.1236. [DOI] [PubMed] [Google Scholar]
  17. Griffin G. E., Leung K., Folks T. M., Kunkel S., Nabel G. J. Activation of HIV gene expression during monocyte differentiation by induction of NF-kappa B. Nature. 1989 May 4;339(6219):70–73. doi: 10.1038/339070a0. [DOI] [PubMed] [Google Scholar]
  18. Hatzigeorgiou D. E., He S., Sobel J., Grabstein K. H., Hafner A., Ho J. L. IL-6 down-modulates the cytokine-enhanced antileishmanial activity in human macrophages. J Immunol. 1993 Oct 1;151(7):3682–3692. [PubMed] [Google Scholar]
  19. Hearst N., Hulley S. B. Preventing the heterosexual spread of AIDS. Are we giving our patients the best advice? JAMA. 1988 Apr 22;259(16):2428–2432. [PubMed] [Google Scholar]
  20. Ho D. D., Moudgil T., Alam M. Quantitation of human immunodeficiency virus type 1 in the blood of infected persons. N Engl J Med. 1989 Dec 14;321(24):1621–1625. doi: 10.1056/NEJM198912143212401. [DOI] [PubMed] [Google Scholar]
  21. Ho D. D., Schooley R. T., Rota T. R., Kaplan J. C., Flynn T., Salahuddin S. Z., Gonda M. A., Hirsch M. S. HTLV-III in the semen and blood of a healthy homosexual man. Science. 1984 Oct 26;226(4673):451–453. doi: 10.1126/science.6208608. [DOI] [PubMed] [Google Scholar]
  22. Klebanoff S. J., Coombs R. W. Viricidal effect of polymorphonuclear leukocytes on human immunodeficiency virus-1. Role of the myeloperoxidase system. J Clin Invest. 1992 Jun;89(6):2014–2017. doi: 10.1172/JCI115810. [DOI] [PMC free article] [PubMed] [Google Scholar]
  23. Kreiss J., Ngugi E., Holmes K., Ndinya-Achola J., Waiyaki P., Roberts P. L., Ruminjo I., Sajabi R., Kimata J., Fleming T. R. Efficacy of nonoxynol 9 contraceptive sponge use in preventing heterosexual acquisition of HIV in Nairobi prostitutes. JAMA. 1992 Jul 22;268(4):477–482. [PubMed] [Google Scholar]
  24. Krieger J. N., Coombs R. W., Collier A. C., Ross S. O., Chaloupka K., Cummings D. K., Murphy V. L., Corey L. Recovery of human immunodeficiency virus type 1 from semen: minimal impact of stage of infection and current antiviral chemotherapy. J Infect Dis. 1991 Feb;163(2):386–388. doi: 10.1093/infdis/163.2.386. [DOI] [PubMed] [Google Scholar]
  25. Laga M., Manoka A., Kivuvu M., Malele B., Tuliza M., Nzila N., Goeman J., Behets F., Batter V., Alary M. Non-ulcerative sexually transmitted diseases as risk factors for HIV-1 transmission in women: results from a cohort study. AIDS. 1993 Jan;7(1):95–102. doi: 10.1097/00002030-199301000-00015. [DOI] [PubMed] [Google Scholar]
  26. Laga M., Manoka A., Kivuvu M., Malele B., Tuliza M., Nzila N., Goeman J., Behets F., Batter V., Alary M. Non-ulcerative sexually transmitted diseases as risk factors for HIV-1 transmission in women: results from a cohort study. AIDS. 1993 Jan;7(1):95–102. doi: 10.1097/00002030-199301000-00015. [DOI] [PubMed] [Google Scholar]
  27. Laurence J., Grimison B., Rodriguez-Alfageme C., Astrin S. M. A model system for regulation of chronic HIV-1 infection in peripheral B lymphocytes. Virology. 1993 Oct;196(2):433–441. doi: 10.1006/viro.1993.1499. [DOI] [PubMed] [Google Scholar]
  28. Laurence J. Molecular interactions among herpesviruses and human immunodeficiency viruses. J Infect Dis. 1990 Aug;162(2):338–346. doi: 10.1093/infdis/162.2.338. [DOI] [PubMed] [Google Scholar]
  29. Legrand-Poels S., Vaira D., Pincemail J., van de Vorst A., Piette J. Activation of human immunodeficiency virus type 1 by oxidative stress. AIDS Res Hum Retroviruses. 1990 Dec;6(12):1389–1397. doi: 10.1089/aid.1990.6.1389. [DOI] [PubMed] [Google Scholar]
  30. Levy J. A. The transmission of HIV and factors influencing progression to AIDS. Am J Med. 1993 Jul;95(1):86–100. doi: 10.1016/0002-9343(93)90237-j. [DOI] [PubMed] [Google Scholar]
  31. Miller C. J., Alexander N. J., Gettie A., Hendrickx A. G., Marx P. A. The effect of contraceptives containing nonoxynol-9 on the genital transmission of simian immunodeficiency virus in rhesus macaques. Fertil Steril. 1992 May;57(5):1126–1128. [PubMed] [Google Scholar]
  32. Newburger P. E., Chovaniec M. E., Greenberger J. S., Cohen H. J. Functional changes in human leukemic cell line HL-60. A model for myeloid differentiation. J Cell Biol. 1979 Aug;82(2):315–322. doi: 10.1083/jcb.82.2.315. [DOI] [PMC free article] [PubMed] [Google Scholar]
  33. Niruthisard S., Roddy R. E., Chutivongse S. The effects of frequent nonoxynol-9 use on the vaginal and cervical mucosa. Sex Transm Dis. 1991 Jul-Sep;18(3):176–179. doi: 10.1097/00007435-199107000-00010. [DOI] [PubMed] [Google Scholar]
  34. Niruthisard S., Roddy R. E., Chutivongse S. Use of nonoxynol-9 and reduction in rate of gonococcal and chlamydial cervical infections. Lancet. 1992 Jun 6;339(8806):1371–1375. doi: 10.1016/0140-6736(92)91195-e. [DOI] [PubMed] [Google Scholar]
  35. Ou C. Y., McDonough S. H., Cabanas D., Ryder T. B., Harper M., Moore J., Schochetman G. Rapid and quantitative detection of enzymatically amplified HIV-1 DNA using chemiluminescent oligonucleotide probes. AIDS Res Hum Retroviruses. 1990 Nov;6(11):1323–1329. doi: 10.1089/aid.1990.6.1323. [DOI] [PubMed] [Google Scholar]
  36. Pepin J., Plummer F. A., Brunham R. C., Piot P., Cameron D. W., Ronald A. R. The interaction of HIV infection and other sexually transmitted diseases: an opportunity for intervention. AIDS. 1989 Jan;3(1):3–9. [PubMed] [Google Scholar]
  37. Peterman T. A., Stoneburner R. L., Allen J. R., Jaffe H. W., Curran J. W. Risk of human immunodeficiency virus transmission from heterosexual adults with transfusion-associated infections. JAMA. 1988 Jan 1;259(1):55–58. [PubMed] [Google Scholar]
  38. Plummer F. A., Simonsen J. N., Cameron D. W., Ndinya-Achola J. O., Kreiss J. K., Gakinya M. N., Waiyaki P., Cheang M., Piot P., Ronald A. R. Cofactors in male-female sexual transmission of human immunodeficiency virus type 1. J Infect Dis. 1991 Feb;163(2):233–239. doi: 10.1093/infdis/163.2.233. [DOI] [PubMed] [Google Scholar]
  39. 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]
  40. 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]
  41. Rosenberg M. J., Gollub E. L. Commentary: methods women can use that may prevent sexually transmitted disease, including HIV. Am J Public Health. 1992 Nov;82(11):1473–1478. doi: 10.2105/ajph.82.11.1473. [DOI] [PMC free article] [PubMed] [Google Scholar]
  42. Rothermel C. D., Schachter J., Lavrich P., Lipsitz E. C., Francus T. Chlamydia trachomatis-induced production of interleukin-1 by human monocytes. Infect Immun. 1989 Sep;57(9):2705–2711. doi: 10.1128/iai.57.9.2705-2711.1989. [DOI] [PMC free article] [PubMed] [Google Scholar]
  43. Schreck R., Grassmann R., Fleckenstein B., Baeuerle P. A. Antioxidants selectively suppress activation of NF-kappa B by human T-cell leukemia virus type I Tax protein. J Virol. 1992 Nov;66(11):6288–6293. doi: 10.1128/jvi.66.11.6288-6293.1992. [DOI] [PMC free article] [PubMed] [Google Scholar]
  44. Schreck R., Rieber P., Baeuerle P. A. Reactive oxygen intermediates as apparently widely used messengers in the activation of the NF-kappa B transcription factor and HIV-1. EMBO J. 1991 Aug;10(8):2247–2258. doi: 10.1002/j.1460-2075.1991.tb07761.x. [DOI] [PMC free article] [PubMed] [Google Scholar]
  45. Taylor-Wiedeman J., Hayhurst G. P., Sissons J. G., Sinclair J. H. Polymorphonuclear cells are not sites of persistence of human cytomegalovirus in healthy individuals. J Gen Virol. 1993 Feb;74(Pt 2):265–268. doi: 10.1099/0022-1317-74-2-265. [DOI] [PubMed] [Google Scholar]
  46. Wiley J. A., Herschkorn S. J., Padian N. S. Heterogeneity in the probability of HIV transmission per sexual contact: the case of male-to-female transmission in penile-vaginal intercourse. Stat Med. 1989 Jan;8(1):93–102. doi: 10.1002/sim.4780080110. [DOI] [PubMed] [Google Scholar]
  47. Zagury D., Bernard J., Leibowitch J., Safai B., Groopman J. E., Feldman M., Sarngadharan M. G., Gallo R. C. HTLV-III in cells cultured from semen of two patients with AIDS. Science. 1984 Oct 26;226(4673):449–451. doi: 10.1126/science.6208607. [DOI] [PubMed] [Google Scholar]

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