Skip to main content
Clinical and Diagnostic Laboratory Immunology logoLink to Clinical and Diagnostic Laboratory Immunology
. 1996 Sep;3(5):493–499. doi: 10.1128/cdli.3.5.493-499.1996

Type 1 and type 2 cytokine profiles in children exposed to or infected with vertically transmitted human immunodeficiency virus.

B N Lee 1, J G Lu 1, M W Kline 1, M Paul 1, M Doyle 1, C Kozinetz 1, W T Shearer 1, J M Reuben 1
PMCID: PMC170395  PMID: 8877124

Abstract

In human immunodeficiency virus (HIV)-infected adults, cytokine production profiles switch from predominantly type 1 (interleukin-2 [IL-2] and gamma interferon [IFN-gamma]) to type 2 (IL-4 and IL-10) cytokines with disease progression. To test this hypothesis in vertically HIV-infected children, we measured cytokine transcription and production in rapid progressors (RPs), seroreverters (SRs), and those children exposed to HIV in utero (P0s). Production of type 1 and type 2 cytokines was measured in peripheral blood mononuclear cell cultures of 8 SR, 25 P0, and 11 RP children. Unstimulated cultures, irrespective of infection and stage of disease, produced similar levels of IL-2, IFN-gamma, IL-4, and IL-10. Upon stimulation with phytohemagglutinin (PHA) plus phorbol-12-myristate-13-acetate (PMA), RP children produced less IL-2 (P < 0.01) and IFN-gamma (P < 0.02) than SR children and also expressed significantly less IFN-gamma mRNA (P < 0.01) than SR children. RP children expressed significantly higher levels of IL-4 mRNA than P0 children (P < 0.03). There were no differences in the production of IL-10 by PHA-PMA-stimulated peripheral blood mononuclear cell cultures among the three groups of children. Our data with these pediatric patients suggest that a deficiency in mitogen-stimulated type 1 cytokine production and excess type 2 cytokine (IL-4) transcription correlate with disease progression. Additional studies with larger sample sizes are needed to test further the hypothesis of the type 1-to-type 2 cytokine switch in children infected with HIV.

Full Text

The Full Text of this article is available as a PDF (435.9 KB).

Selected References

These references are in PubMed. This may not be the complete list of references from this article.

  1. Blanche S., Rouzioux C., Moscato M. L., Veber F., Mayaux M. J., Jacomet C., Tricoire J., Deville A., Vial M., Firtion G. A prospective study of infants born to women seropositive for human immunodeficiency virus type 1. HIV Infection in Newborns French Collaborative Study Group. N Engl J Med. 1989 Jun 22;320(25):1643–1648. doi: 10.1056/NEJM198906223202502. [DOI] [PubMed] [Google Scholar]
  2. Blanche S., Tardieu M., Duliege A., Rouzioux C., Le Deist F., Fukunaga K., Caniglia M., Jacomet C., Messiah A., Griscelli C. Longitudinal study of 94 symptomatic infants with perinatally acquired human immunodeficiency virus infection. Evidence for a bimodal expression of clinical and biological symptoms. Am J Dis Child. 1990 Nov;144(11):1210–1215. doi: 10.1001/archpedi.1990.02150350042021. [DOI] [PubMed] [Google Scholar]
  3. Bryson Y. J., Pang S., Wei L. S., Dickover R., Diagne A., Chen I. S. Clearance of HIV infection in a perinatally infected infant. N Engl J Med. 1995 Mar 30;332(13):833–838. doi: 10.1056/NEJM199503303321301. [DOI] [PubMed] [Google Scholar]
  4. 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]
  5. Chantry C. J., Cooper E. R., Pelton S. I., Zorilla C., Hillyer G. V., Diaz C. Seroreversion in human immunodeficiency virus-exposed but uninfected infants. Pediatr Infect Dis J. 1995 May;14(5):382–387. doi: 10.1097/00006454-199505000-00009. [DOI] [PubMed] [Google Scholar]
  6. 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]
  7. Clerici M., DePalma L., Roilides E., Baker R., Shearer G. M. Analysis of T helper and antigen-presenting cell functions in cord blood and peripheral blood leukocytes from healthy children of different ages. J Clin Invest. 1993 Jun;91(6):2829–2836. doi: 10.1172/JCI116526. [DOI] [PMC free article] [PubMed] [Google Scholar]
  8. Clerici M., Hakim F. T., Venzon D. J., Blatt S., Hendrix C. W., Wynn T. A., Shearer G. M. Changes in interleukin-2 and interleukin-4 production in asymptomatic, human immunodeficiency virus-seropositive individuals. J Clin Invest. 1993 Mar;91(3):759–765. doi: 10.1172/JCI116294. [DOI] [PMC free article] [PubMed] [Google Scholar]
  9. Clerici M., Shearer G. M. A TH1-->TH2 switch is a critical step in the etiology of HIV infection. Immunol Today. 1993 Mar;14(3):107–111. doi: 10.1016/0167-5699(93)90208-3. [DOI] [PubMed] [Google Scholar]
  10. Clerici M., Shearer G. M. The Th1-Th2 hypothesis of HIV infection: new insights. Immunol Today. 1994 Dec;15(12):575–581. doi: 10.1016/0167-5699(94)90220-8. [DOI] [PubMed] [Google Scholar]
  11. Erkeller-Yuksel F. M., Deneys V., Yuksel B., Hannet I., Hulstaert F., Hamilton C., Mackinnon H., Stokes L. T., Munhyeshuli V., Vanlangendonck F. Age-related changes in human blood lymphocyte subpopulations. J Pediatr. 1992 Feb;120(2 Pt 1):216–222. doi: 10.1016/s0022-3476(05)80430-5. [DOI] [PubMed] [Google Scholar]
  12. Graziosi C., Pantaleo G., Gantt K. R., Fortin J. P., Demarest J. F., Cohen O. J., Sékaly R. P., Fauci A. S. Lack of evidence for the dichotomy of TH1 and TH2 predominance in HIV-infected individuals. Science. 1994 Jul 8;265(5169):248–252. doi: 10.1126/science.8023143. [DOI] [PubMed] [Google Scholar]
  13. Gruters R. A., Terpstra F. G., De Jong R., Van Noesel C. J., Van Lier R. A., Miedema F. Selective loss of T cell functions in different stages of HIV infection. Early loss of anti-CD3-induced T cell proliferation followed by decreased anti-CD3-induced cytotoxic T lymphocyte generation in AIDS-related complex and AIDS. Eur J Immunol. 1990 May;20(5):1039–1044. doi: 10.1002/eji.1830200514. [DOI] [PubMed] [Google Scholar]
  14. Hollinger F. B., Bremer J. W., Myers L. E., Gold J. W., McQuay L. Standardization of sensitive human immunodeficiency virus coculture procedures and establishment of a multicenter quality assurance program for the AIDS Clinical Trials Group. The NIH/NIAID/DAIDS/ACTG Virology Laboratories. J Clin Microbiol. 1992 Jul;30(7):1787–1794. doi: 10.1128/jcm.30.7.1787-1794.1992. [DOI] [PMC free article] [PubMed] [Google Scholar]
  15. Hyjek E., Lischner H. W., Hyslop T., Bartkowiak J., Kubin M., Trinchieri G., Kozbor D. Cytokine patterns during progression to AIDS in children with perinatal HIV infection. J Immunol. 1995 Oct 15;155(8):4060–4071. [PubMed] [Google Scholar]
  16. Kline M. W., Paul M. E., Bohannon B., Kozinetz C. A., Shearer W. T. Characteristics of children surviving to 5 years of age or older with vertically acquired HIV infection. Pediatr AIDS HIV Infect. 1995 Dec;6(6):350–353. [PubMed] [Google Scholar]
  17. Koup R. A., Safrit J. T., Cao Y., Andrews C. A., McLeod G., Borkowsky W., Farthing C., Ho D. D. Temporal association of cellular immune responses with the initial control of viremia in primary human immunodeficiency virus type 1 syndrome. J Virol. 1994 Jul;68(7):4650–4655. doi: 10.1128/jvi.68.7.4650-4655.1994. [DOI] [PMC free article] [PubMed] [Google Scholar]
  18. Krasinski K., Borkowsky W., Holzman R. S. Prognosis of human immunodeficiency virus infection in children and adolescents. Pediatr Infect Dis J. 1989 Apr;8(4):216–220. [PubMed] [Google Scholar]
  19. Kruse A., Rink L., Rutenfranz I., Kolanczyk B., Kirchner H. Interferon and lymphokine production by human placental and cord blood cells. J Interferon Res. 1992 Apr;12(2):113–117. doi: 10.1089/jir.1992.12.113. [DOI] [PubMed] [Google Scholar]
  20. Luzuriaga K., Holmes D., Hereema A., Wong J., Panicali D. L., Sullivan J. L. HIV-1-specific cytotoxic T lymphocyte responses in the first year of life. J Immunol. 1995 Jan 1;154(1):433–443. [PubMed] [Google Scholar]
  21. Luzuriaga K., Koup R. A., Pikora C. A., Brettler D. B., Sullivan J. L. Deficient human immunodeficiency virus type 1-specific cytotoxic T cell responses in vertically infected children. J Pediatr. 1991 Aug;119(2):230–236. doi: 10.1016/s0022-3476(05)80732-2. [DOI] [PubMed] [Google Scholar]
  22. Motley D., Meyer M. P., King R. A., Naus G. J. Determination of lymphocyte immunophenotypic values for normal full-term cord blood. Am J Clin Pathol. 1996 Jan;105(1):38–43. doi: 10.1093/ajcp/105.1.38. [DOI] [PubMed] [Google Scholar]
  23. Petersen J. M., Weinberg K. I., Annett G., Church J., Gomperts E., Parkman R. Correction of antigen-specific T-lymphocyte function by recombinant cytokines in children infected with human immunodeficiency virus type 1. J Pediatr. 1992 Oct;121(4):565–568. doi: 10.1016/s0022-3476(05)81145-x. [DOI] [PubMed] [Google Scholar]
  24. Poulin L., Fauchon M., Darveau A., Levy J. A. Inhibition of protein synthesis by the human immunodeficiency virus type 1 nef gene product. J Gen Virol. 1994 Nov;75(Pt 11):2977–2984. doi: 10.1099/0022-1317-75-11-2977. [DOI] [PubMed] [Google Scholar]
  25. Raes M., Alliet P., Gillis P., Zimmermann A., Kortleven J., Magerman K., Peeters V., Rummens J. L. Lymphocyte subpopulations in healthy newborn infants: comparison of cord blood values with values five days after birth. J Pediatr. 1993 Sep;123(3):465–467. doi: 10.1016/s0022-3476(05)81758-5. [DOI] [PubMed] [Google Scholar]
  26. Romagnani S., Del Prete G., Manetti R., Ravina A., Annunziato F., De Carli M., Mazzetti M., Piccinni M. P., D'Elios M. M., Parronchi P. Role of TH1/TH2 cytokines in HIV infection. Immunol Rev. 1994 Aug;140:73–92. doi: 10.1111/j.1600-065x.1994.tb00865.x. [DOI] [PubMed] [Google Scholar]
  27. Salk J., Bretscher P. A., Salk P. L., Clerici M., Shearer G. M. A strategy for prophylactic vaccination against HIV. Science. 1993 May 28;260(5112):1270–1272. doi: 10.1126/science.8098553. [DOI] [PubMed] [Google Scholar]
  28. Salmon M., Kitas G. D., Bacon P. A. Production of lymphokine mRNA by CD45R+ and CD45R- helper T cells from human peripheral blood and by human CD4+ T cell clones. J Immunol. 1989 Aug 1;143(3):907–912. [PubMed] [Google Scholar]
  29. Scott G. B., Hutto C., Makuch R. W., Mastrucci M. T., O'Connor T., Mitchell C. D., Trapido E. J., Parks W. P. Survival in children with perinatally acquired human immunodeficiency virus type 1 infection. N Engl J Med. 1989 Dec 28;321(26):1791–1796. doi: 10.1056/NEJM198912283212604. [DOI] [PubMed] [Google Scholar]
  30. Street N. E., Mosmann T. R. Functional diversity of T lymphocytes due to secretion of different cytokine patterns. FASEB J. 1991 Feb;5(2):171–177. doi: 10.1096/fasebj.5.2.1825981. [DOI] [PubMed] [Google Scholar]
  31. Viganó A., Principi N., Villa M. L., Riva C., Crupi L., Trabattoni D., Shearer G. M., Clerici M. Immunologic characterization of children vertically infected with human immunodeficiency virus, with slow or rapid disease progression. J Pediatr. 1995 Mar;126(3):368–374. doi: 10.1016/s0022-3476(95)70450-7. [DOI] [PubMed] [Google Scholar]
  32. Wilson C. B., Westall J., Johnston L., Lewis D. B., Dower S. K., Alpert A. R. Decreased production of interferon-gamma by human neonatal cells. Intrinsic and regulatory deficiencies. J Clin Invest. 1986 Mar;77(3):860–867. doi: 10.1172/JCI112383. [DOI] [PMC free article] [PubMed] [Google Scholar]
  33. Wynn T. A., Eltoum I., Cheever A. W., Lewis F. A., Gause W. C., Sher A. Analysis of cytokine mRNA expression during primary granuloma formation induced by eggs of Schistosoma mansoni. J Immunol. 1993 Aug 1;151(3):1430–1440. [PubMed] [Google Scholar]

Articles from Clinical and Diagnostic Laboratory Immunology are provided here courtesy of American Society for Microbiology (ASM)

RESOURCES