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Part II. Diagnostics and Antiviral Therapy. Antivirals

Inhibition of Cytomegalovirus in vitro and in vivo by the Experimental Immunosuppressive Agent Leflunomide

Waldman W.J.a · Knight D.A.a · Blinder L.b · Shen J.b · Lurain N.S.c · Miller D.M.a · Sedmak D.D.a · Williams J.W.b · Chong A.S.-F.b,c

Author affiliations

aDepartment of Pathology, The Ohio State University College of Medicine and Public Health, Columbus, Ohio, bDepartment of General Surgery, Rush Presbyterian-St. Luke’s Medical Center, and cDepartment of Microbiology/Immunology, Rush University, Chicago, Ill., USA

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Intervirology 1999;42:412–418

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Article / Publication Details

First-Page Preview
Abstract of Part II. Diagnostics and Antiviral Therapy. Antivirals

Published online: February 28, 2000
Issue release date: February 2000

Number of Print Pages: 7
Number of Figures: 0
Number of Tables: 0

ISSN: 0300-5526 (Print)
eISSN: 1423-0100 (Online)

For additional information: https://www.karger.com/INT

Abstract

Despite progress in antiviral chemotherapy, cytomegalovirus (CMV) remains a major cause of morbidity and mortality among pharmacologically immunosuppressed transplant recipients, frequently engaging the clinician in a struggle to balance graft preservation with control of CMV disease. Leflunomide, an inhibitor of protein kinase activity and pyrimidine synthesis, is an experimental immunosuppressive agent effective against acute and chronic rejection in animal models. Herein we summarize our recent studies demonstrating that leflunomide inhibits the production of multiple clinical CMV isolates (including multi-drug-resistant virus) in both human fibroblasts and endothelial cells. In contrast to all other anti-CMV drugs currently in use, leflunomide does not inhibit viral DNA synthesis, but rather appears to interfere with virion assembly. Finally, preliminary studies in a rat model suggest that this agent reduces viral load in vivo. These findings imply that leflunomide, an effective immunosuppressive agent, shows potential to concurrently attenuate a major complication of immunosuppression, CMV disease, by a novel mechanism of antiviral activity.

© 2000 S. Karger AG, Basel


References

  1. Alford CA, Britt WJ: Cytomegalovirus; in Roizman B, Whitley RJ, Lopez C (eds): The Human Herpesviruses. New York, Raven Press, 1993, pp 227–255.
  2. Grattan MT, Moreno-Cabral CE, Starnes VA, Oyer PE, Stinson EB, Shumway NE: Cytomegalovirus infection is associated with cardiac allograft rejection and atherosclerosis. JAMA 1989;261:3561–3566.
  3. von Willebrand E, Pettersson E, Ahonen J, Häyry P: CMV infection, class II antigen expression, and human kidney allograft rejection. Transplantation 1986;42:364–367.
  4. Crumpacker CS: Ganciclovir. Engl J Med 1996;335:721–729.
  5. Lalezari JP, Drew WL, Glutzer E, James C, Miner D, Flaherty J, Fisher K, Cundy J, Hannigan JC, Jaffe HS: (S)-1-[3-hydroxy-2(phosphonylmethoxy)propyl]cytosine (cidofovir): Results of a phase I/II study of a novel antiviral nucleotide analogue. J Infect Dis 1995;171:788–796.
  6. Wagstaff AJ, Bryson HM: Foscarnet: A reappraisal of its antiviral activity, pharmacokinetic properties and therapeutic use in immunocompromised patients with viral infections. Drugs 1994;48:199–226.
  7. Xiong X, Smith JL, Chen MS: Effect of incorporation of cidofovir into DNA by human cytomegalovirus DNA polymerase on DNA elongation. Antimicrob Agents Chemother 1997;41:594–599.
    External Resources
  8. Baldanti F, Underwood MR, Stanat SC, Biron KK, Chou S, Sarasini A, Silini E, Gerna G: Single amino acid changes in the DNA polymerase confer foscarnet resistance and slow-growth phenotype, while mutations in the UL97-encoded phosphotransferase confer ganciclovir resistance in three double-resistant human cytomegalovirus strains recovered from patients with AIDS. J Virol 1996;70:1390–1395.
  9. Erice A, Gil-Roda C, Pérez JL, Balfour HH, Jr, Sannerud KJ, Hanson MN, Boivin G, Chou S: Antiviral susceptibilities and analysis of UL97 and DNA polymerase sequences of clinical cytomegalovirus isolates from immunocompromised patients. J Infect Dis 1997;175:1087–1092.
    External Resources
  10. Tatarowicz WA, Lurain NS, Thompson KD: A ganciclovir-resistant clinical isolate of human cytomegalovirus exhibiting cross-resistance to other DNA polymerase inhibitors. J Infect Dis 1992;166:904–907.
  11. McChesney L, Xiao F, Sankary H, Foster P, Sharma S, Haklin M, Williams J: An evaluation of leflunomide in the canine renal transplantation model. Transplantation 1994;57:1717–1722.
    External Resources
  12. Williams JW, Xiao F, Foster P, Clardy C, McChesney L, Sankary H, Chong As-F: Leflunomide in experimental transplantation: Control of rejection and alloantibody production, reversal of acute rejection and interaction with cyclosporine. Transplantation 1994;57:1223–1231.
    External Resources
  13. Xiao F, Chong A, Shen J, Yang J, Short J, Foster P, Sankary H, Jensik S, Mital D, McChesney L, Koukoulis G, Williams JW: Pharmacologically induced regression of chronic transplant rejection. Transplantation 1995;60:1065–1072.
    External Resources
  14. Bartlett RR, Dimitrijevic M, Mattar T, Zielinske T, Germann T, Rüde E, Thoenes GH, Küchle CCA, Schorlemmer H-U, Bremer E, Finnegan A, Schleyerbach R: Leflunomide (HWA 486), a novel immunomodulating compound for the treatment of autoimmune disorders and reactions leading to transplantation rejection. Agents Actions 1991;32:10–21.
    External Resources
  15. Xu X, Williams J, Bremer E, Finnegan A, Chong A: Inhibition of protein tyrosine phosphorylation in T cells by novel immunosuppressive agent, leflunomide. J Biol Chem 1995;270:12398–12403.
  16. Williamson RA, Yea CM, Robson PA, Curnock AP, Gadher S, Hambleton AB, Woodward K, Bruneau J-M, Hambleton P, Moss D, Thomson TA, Spinella-Jaegle S, Morand P, Courtin O, Sautes C, Westwood R, Hecend T, Kuo EA, Ruuth E: Dihydroorotate dehydrogenase is a high affinity binding protein for A77 1726 and mediator of a range of biological effects of the immunomodulatory compound. J Biol Chem 1995;270:22467–22472.
  17. Mocarski ES Jr: Cytomegalovirus biology and replication: in Roizman B, Whitley RJ, Lopez C (eds): The Human Herpesviruses. New York, Raven Press, 1993, pp 173–226.
  18. Myerson D, Hackman RC, Nelson JA, Ward DC, McDougall JK: Widespread presence of histologically occult cytomegalovirus. Hum Pathol 1984;15:430–439.
  19. Sinzger C, Müntefering H, Löning T, Stöss H, Plachter B, Jahn G: Cell types infected in human cytomegalovirus placentitis identified by immunohistochemical double staining. Virchows Archiv A Pathol Anat 1993;423:249–256.
  20. Waldman WJ, Roberts WH, Davis DH, Williams MV, Sedmak DD, Stephens RE: Preservation of natural endothelial cytopathogenicity of cytomegalovirus by propagation in endothelial cells. Arch Virol 1991;117:143–164.
    External Resources
  21. Waldman WJ, Knight DA, Lurain NS, Miller DM, Sedmak DD, Williams JW, Chong AS-F: Novel mechanism of inhibition of CMV by the experimental immunosuppressive agent leflunomide. Transplantation 1999;68:814–825.
    External Resources
  22. Chong AS-F, Finnegan A, Jiang XL, Gebel H, Sankary HN, Foster P, Williams JW: Leflunomide, a novel immunosuppressive agent. The mechanism of inhibition of T cell proliferation. Transplantation 1993;55:1361–1366.
  23. Chong AS-F, Huang W, Liu W, Luo J, Shen J, Xu W, Ma L, Binder L, Xiao F, Xu X, Clardy C, Foster P, Williams JW: In vivo activity of leflunomide: Pharmacokinetic analyses and mechanism of immunosuppression. Transplantation 1999;68:100–109.
    External Resources
  24. Waldman WJ, Knight DA, Huang EH, Sedmak DD: Bidirectional transmission of infectious cytomegalovirus between monocytes and vascular endothelial cells: An in vitro model. J Infect Dis 1995;171:263–272.
    External Resources
  25. Khym JX: An analytical system for rapid separation of tissue nucleotides at low pressures on conventional anion exchanges. Clin Chem 1975;21:1245–1252.
  26. Gibson W: Structure and assembly of the virion. Intervirology 1996;39:389–400.
    External Resources
  27. Bruggeman CA, Debie WMH, Grauls G, Majoor G, Van Boven CPA: 1983. Infection of laboratory rats with a new cytomegalo-like virus. Arch Virol 1983;76:189–199.
  28. Waldman WJ, Blinder L, Knight DA, Shen J, Lurain NS, Miller DM, Sedmak DD, Williams JW, Chong AS-F: Inhibition of CMV in vitro and in vivo by the experimental immunosuppressive agent leflunomide. J Clin Virol 1999;12:174.
  29. Elder RT, Xu X, Williams JW, Gong J, Finnegan A, Chong AS-F: The immunosuppressive drug metabolite of leflunomide, A77 1726, affects murine T cells through two biochemical mechanisms. J Immunol 1997;159:22–27.
    External Resources
  30. Xu X, Williams JW, Gong H, Finnegan A, Chong AS-F: Two activities of the immunosuppressant, leflunomide: Inhibition of pyrimidine synthesis and protein tyrosine phosphorylation. Biochem Pharmacol 1996;52:527–534.
  31. Littler E, Stuart AD, Chee MS: Human cytomegalovirus UL97 open reading frame encodes a protein that phosphorylates the antiviral nucleoside analogue ganciclovir. Nature 1992;358:160–162.
    External Resources
  32. Sullivan V, Talarico CL, Stanat SC, Davis M, Coen DM, Biron KK: A protein kinase homologue controls phosphorylation of ganciclovir in human cytomegalovirus-infected cells. Nature 1992;358:162–164.
  33. Lalezari JP, Stagg RJ, Kuppermann BD, Holland GN, Kramer F, Ives DV, Youle M, Robinson MR, Drew WL, Jaffe HS: Intravenous cidofovir for peripheral cytomegalovirus retinitis in patients with AIDS. A randomized, controlled trial. Ann Intern Med 1997;126:257–263.
  34. Mladenovic V, Domljan Z, Rozman B, Jajic I, Mihajlovic D, Dordevic J, Popovic M, Dimitrijevic M, Zivdovic M, Campion G, Musikic P, Löw-Friedrich I, Oed C, Seifert H, Strand V: Safety and effectiveness of leflunomide in the treatment of patients with active rheumatoid arthritis. Arthritis Rheum 1995;38:1595–1603.
    External Resources

Article / Publication Details

First-Page Preview
Abstract of Part II. Diagnostics and Antiviral Therapy. Antivirals

Published online: February 28, 2000
Issue release date: February 2000

Number of Print Pages: 7
Number of Figures: 0
Number of Tables: 0

ISSN: 0300-5526 (Print)
eISSN: 1423-0100 (Online)

For additional information: https://www.karger.com/INT


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