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. 1997 Oct;71(10):7799–7803. doi: 10.1128/jvi.71.10.7799-7803.1997

Interleukin-12 exhibits potent antiviral activity in experimental herpesvirus infections.

J A Carr 1, J Rogerson 1, M J Mulqueen 1, N A Roberts 1, R F Booth 1
PMCID: PMC192132  PMID: 9311865

Abstract

The prophylactic and therapeutic efficacy of interleukin-12 was studied by using murine models of herpes simplex virus infection. Prophylactic administration consisted of two intraperitoneal doses of interleukin-12 given 48 and 24 h prior to infection. Therapeutic intraperitoneal administration of interleukin-12 commenced 6 h after the mice were infected with herpes simplex virus and was continued daily for a total of 5 days. Interleukin-12 therapy improved the survival rates of mice with systemic herpes simplex virus infection compared with those of placebo-treated infected mice. Subcutaneous administration of interleukin-12 also improved the rate of survival of mice after systemic herpes simplex virus infection, although higher doses were required to give comparable effects. Combined prophylactic and therapeutic administration of interleukin-12 produced the greatest effect on survival after an otherwise lethal systemic infection. Intraperitoneal administration of interleukin-12 for 2 days before and 3 days after systemic infection with herpes simplex virus resulted in survival of 80% of the mice. These surviving mice were resistant to subsequent reinfection with herpes simplex virus. Such resistance was apparently specific for herpes simplex virus infection, since a second group of survivors succumbed to a lethal infection with murine cytomegalovirus. Infectious virus was recovered from lumbar ganglia explants dissected from survivors of prophylactic interleukin-12 therapy and cultured for 5 days in vitro, suggesting that interleukin-12 treatment did not prevent the establishment of latent herpes simplex virus infection. One action of interleukin-12 may be to enhance natural killer cell-mediated clearance of the virus. However, interleukin-12 therapy was also effective in mice carrying the beige mutation, which reduces natural killer cell lytic activity, suggesting that interleukin-12 has additional activities in vivo.

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Selected References

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  1. Bi Z., Quandt P., Komatsu T., Barna M., Reiss C. S. IL-12 promotes enhanced recovery from vesicular stomatitis virus infection of the central nervous system. J Immunol. 1995 Dec 15;155(12):5684–5689. [PubMed] [Google Scholar]
  2. Cavanaugh V. J., Guidotti L. G., Chisari F. V. Interleukin-12 inhibits hepatitis B virus replication in transgenic mice. J Virol. 1997 Apr;71(4):3236–3243. doi: 10.1128/jvi.71.4.3236-3243.1997. [DOI] [PMC free article] [PubMed] [Google Scholar]
  3. Chehimi J., Starr S. E., Frank I., D'Andrea A., Ma X., MacGregor R. R., Sennelier J., Trinchieri G. Impaired interleukin 12 production in human immunodeficiency virus-infected patients. J Exp Med. 1994 Apr 1;179(4):1361–1366. doi: 10.1084/jem.179.4.1361. [DOI] [PMC free article] [PubMed] [Google Scholar]
  4. Chehimi J., Starr S. E., Frank I., Rengaraju M., Jackson S. J., Llanes C., Kobayashi M., Perussia B., Young D., Nickbarg E. Natural killer (NK) cell stimulatory factor increases the cytotoxic activity of NK cells from both healthy donors and human immunodeficiency virus-infected patients. J Exp Med. 1992 Mar 1;175(3):789–796. doi: 10.1084/jem.175.3.789. [DOI] [PMC free article] [PubMed] [Google Scholar]
  5. Chehimi J., Valiante N. M., D'Andrea A., Rengaraju M., Rosado Z., Kobayashi M., Perussia B., Wolf S. F., Starr S. E., Trinchieri G. Enhancing effect of natural killer cell stimulatory factor (NKSF/interleukin-12) on cell-mediated cytotoxicity against tumor-derived and virus-infected cells. Eur J Immunol. 1993 Aug;23(8):1826–1830. doi: 10.1002/eji.1830230814. [DOI] [PubMed] [Google Scholar]
  6. Chougnet C., Wynn T. A., Clerici M., Landay A. L., Kessler H. A., Rusnak J., Melcher G. P., Sher A., Shearer G. M. Molecular analysis of decreased interleukin-12 production in persons infected with human immunodeficiency virus. J Infect Dis. 1996 Jul;174(1):46–53. doi: 10.1093/infdis/174.1.46. [DOI] [PubMed] [Google Scholar]
  7. Coutelier J. P., Van Broeck J., Wolf S. F. Interleukin-12 gene expression after viral infection in the mouse. J Virol. 1995 Mar;69(3):1955–1958. doi: 10.1128/jvi.69.3.1955-1958.1995. [DOI] [PMC free article] [PubMed] [Google Scholar]
  8. Germann T., Gately M. K., Schoenhaut D. S., Lohoff M., Mattner F., Fischer S., Jin S. C., Schmitt E., Rüde E. Interleukin-12/T cell stimulating factor, a cytokine with multiple effects on T helper type 1 (Th1) but not on Th2 cells. Eur J Immunol. 1993 Aug;23(8):1762–1770. doi: 10.1002/eji.1830230805. [DOI] [PubMed] [Google Scholar]
  9. Iwasaka T., Sheridan J. F., Aurelian L. Immunity to herpes simplex virus type 2: recurrent lesions are associated with the induction of suppressor cells and soluble suppressor factors. Infect Immun. 1983 Dec;42(3):955–964. doi: 10.1128/iai.42.3.955-964.1983. [DOI] [PMC free article] [PubMed] [Google Scholar]
  10. Jonjić S., Pavić I., Polić B., Crnković I., Lucin P., Koszinowski U. H. Antibodies are not essential for the resolution of primary cytomegalovirus infection but limit dissemination of recurrent virus. J Exp Med. 1994 May 1;179(5):1713–1717. doi: 10.1084/jem.179.5.1713. [DOI] [PMC free article] [PubMed] [Google Scholar]
  11. Kobayashi M., Fitz L., Ryan M., Hewick R. M., Clark S. C., Chan S., Loudon R., Sherman F., Perussia B., Trinchieri G. Identification and purification of natural killer cell stimulatory factor (NKSF), a cytokine with multiple biologic effects on human lymphocytes. J Exp Med. 1989 Sep 1;170(3):827–845. doi: 10.1084/jem.170.3.827. [DOI] [PMC free article] [PubMed] [Google Scholar]
  12. Matsuo R., Kobayashi M., Herndon D. N., Pollard R. B., Suzuki F. Interleukin-12 protects thermally injured mice from herpes simplex virus type 1 infection. J Leukoc Biol. 1996 May;59(5):623–630. doi: 10.1002/jlb.59.5.623. [DOI] [PubMed] [Google Scholar]
  13. McKendall R. R. Delayed IgG-mediated clearance of herpes simplex virus type 1 from the CNS but not footpad during the early stages of infection: possible result of relative integrity of the blood-brain barrier. J Gen Virol. 1983 Sep;64(Pt 9):1965–1972. doi: 10.1099/0022-1317-64-9-1965. [DOI] [PubMed] [Google Scholar]
  14. Milich D. R., Wolf S. F., Hughes J. L., Jones J. E. Interleukin 12 suppresses autoantibody production by reversing helper T-cell phenotype in hepatitis B e antigen transgenic mice. Proc Natl Acad Sci U S A. 1995 Jul 18;92(15):6847–6851. doi: 10.1073/pnas.92.15.6847. [DOI] [PMC free article] [PubMed] [Google Scholar]
  15. Murray H. W., Hariprashad J. Interleukin 12 is effective treatment for an established systemic intracellular infection: experimental visceral leishmaniasis. J Exp Med. 1995 Jan 1;181(1):387–391. doi: 10.1084/jem.181.1.387. [DOI] [PMC free article] [PubMed] [Google Scholar]
  16. Nash A. A., Field H. J., Quartey-Papafio R. Cell-mediated immunity in herpes simplex virus-infected mice: induction, characterization and antiviral effects of delayed type hypersensitivity. J Gen Virol. 1980 Jun;48(Pt 2):351–357. doi: 10.1099/0022-1317-48-2-351. [DOI] [PubMed] [Google Scholar]
  17. Oakes J. E. Role for cell-mediated immunity in the resistance of mice to subcutaneous herpes simplex virus infection. Infect Immun. 1975 Jul;12(1):166–172. doi: 10.1128/iai.12.1.166-172.1975. [DOI] [PMC free article] [PubMed] [Google Scholar]
  18. Orange J. S., Biron C. A. An absolute and restricted requirement for IL-12 in natural killer cell IFN-gamma production and antiviral defense. Studies of natural killer and T cell responses in contrasting viral infections. J Immunol. 1996 Feb 1;156(3):1138–1142. [PubMed] [Google Scholar]
  19. Orange J. S., Salazar-Mather T. P., Opal S. M., Spencer R. L., Miller A. H., McEwen B. S., Biron C. A. Mechanism of interleukin 12-mediated toxicities during experimental viral infections: role of tumor necrosis factor and glucocorticoids. J Exp Med. 1995 Mar 1;181(3):901–914. doi: 10.1084/jem.181.3.901. [DOI] [PMC free article] [PubMed] [Google Scholar]
  20. Orange J. S., Wolf S. F., Biron C. A. Effects of IL-12 on the response and susceptibility to experimental viral infections. J Immunol. 1994 Feb 1;152(3):1253–1264. [PubMed] [Google Scholar]
  21. Ozmen L., Aguet M., Trinchieri G., Garotta G. The in vivo antiviral activity of interleukin-12 is mediated by gamma interferon. J Virol. 1995 Dec;69(12):8147–8150. doi: 10.1128/jvi.69.12.8147-8150.1995. [DOI] [PMC free article] [PubMed] [Google Scholar]
  22. Peto R., Pike M. C., Armitage P., Breslow N. E., Cox D. R., Howard S. V., Mantel N., McPherson K., Peto J., Smith P. G. Design and analysis of randomized clinical trials requiring prolonged observation of each patient. II. analysis and examples. Br J Cancer. 1977 Jan;35(1):1–39. doi: 10.1038/bjc.1977.1. [DOI] [PMC free article] [PubMed] [Google Scholar]
  23. Tang Y. W., Graham B. S. Interleukin-12 treatment during immunization elicits a T helper cell type 1-like immune response in mice challenged with respiratory syncytial virus and improves vaccine immunogenicity. J Infect Dis. 1995 Sep;172(3):734–738. doi: 10.1093/infdis/172.3.734. [DOI] [PubMed] [Google Scholar]
  24. Taylor J. L., Tom P., Guy J., Selvarajan R. M., O'Brien W. J. Regulation of herpes simplex virus thymidine kinase in cells treated with a synergistic antiviral combination of alpha interferon and acyclovir. Antimicrob Agents Chemother. 1994 Apr;38(4):853–856. doi: 10.1128/aac.38.4.853. [DOI] [PMC free article] [PubMed] [Google Scholar]
  25. Than S., Hu R., Oyaizu N., Romano J., Wang X., Sheikh S., Pahwa S. Cytokine pattern in relation to disease progression in human immunodeficiency virus-infected children. J Infect Dis. 1997 Jan;175(1):47–56. doi: 10.1093/infdis/175.1.47. [DOI] [PubMed] [Google Scholar]
  26. Wachsman M., Luo J. H., Aurelian L., Paoletti E. Protection from herpes simplex virus type 2 is associated with T cells involved in delayed type hypersensitivity that recognize glycosylation-related epitopes on glycoprotein D. Vaccine. 1992;10(7):447–454. doi: 10.1016/0264-410x(92)90393-x. [DOI] [PubMed] [Google Scholar]
  27. Wolf S. F., Sieburth D., Sypek J. Interleukin 12: a key modulator of immune function. Stem Cells. 1994 Mar;12(2):154–168. doi: 10.1002/stem.5530120203. [DOI] [PubMed] [Google Scholar]
  28. Wolf S. F., Temple P. A., Kobayashi M., Young D., Dicig M., Lowe L., Dzialo R., Fitz L., Ferenz C., Hewick R. M. Cloning of cDNA for natural killer cell stimulatory factor, a heterodimeric cytokine with multiple biologic effects on T and natural killer cells. J Immunol. 1991 May 1;146(9):3074–3081. [PubMed] [Google Scholar]
  29. Yoo J., Chen H., Kraus T., Hirsch D., Polyak S., George I., Sperber K. Altered cytokine production and accessory cell function after HIV-1 infection. J Immunol. 1996 Aug 1;157(3):1313–1320. [PubMed] [Google Scholar]

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