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. 1991 Nov;35(11):2191–2197. doi: 10.1128/aac.35.11.2191

Ganciclovir-resistant cytomegalovirus clinical isolates: mode of resistance to ganciclovir.

S C Stanat 1, J E Reardon 1, A Erice 1, M C Jordan 1, W L Drew 1, K K Biron 1
PMCID: PMC245358  PMID: 1666492

Abstract

Cytomegalovirus strains with reduced in vitro susceptibilities to ganciclovir have been recovered from patients who failed long-term ganciclovir therapy. The ganciclovir-resistant clinical isolates in this study were unable to induce ganciclovir phosphorylation in virus-infected cells. The viral DNA polymerase function appeared unaltered in one genetically pure ganciclovir-resistant strain, compared with that of its wild-type ganciclovir-sensitive counterpart. All nine of the ganciclovir-resistant strains were susceptible to foscarnet. Moreover, these strains were sensitive to inhibition both by vidarabine and 1-(2'-deoxy-2'-fluoro-beta-D-arabinofuranosyl)-5-iodocytosine (FIAC), antiviral agents that are activated by cellular enzymes, and by (S)-1(3-hydroxy-2-phosphonylmethoxypropyl)cytosine (HPMPC), which is a monophosphate nucleoside analog. The in vitro resistance to ganciclovir of the ganciclovir-resistant clinical isolates studied was attributed to the inability of the cells infected with these isolates to phosphorylate ganciclovir; the virally encoded DNA polymerase did not appear to play a role in this ganciclovir resistance.

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Selected References

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

  1. Balfour H. H., Jr, Chace B. A., Stapleton J. T., Simmons R. L., Fryd D. S. A randomized, placebo-controlled trial of oral acyclovir for the prevention of cytomegalovirus disease in recipients of renal allografts. N Engl J Med. 1989 May 25;320(21):1381–1387. doi: 10.1056/NEJM198905253202105. [DOI] [PubMed] [Google Scholar]
  2. Biron K. K., Fyfe J. A., Stanat S. C., Leslie L. K., Sorrell J. B., Lambe C. U., Coen D. M. A human cytomegalovirus mutant resistant to the nucleoside analog 9-([2-hydroxy-1-(hydroxymethyl)ethoxy]methyl)guanine (BW B759U) induces reduced levels of BW B759U triphosphate. Proc Natl Acad Sci U S A. 1986 Nov;83(22):8769–8773. doi: 10.1073/pnas.83.22.8769. [DOI] [PMC free article] [PubMed] [Google Scholar]
  3. Biron K. K., Stanat S. C., Sorrell J. B., Fyfe J. A., Keller P. M., Lambe C. U., Nelson D. J. Metabolic activation of the nucleoside analog 9-[( 2-hydroxy-1-(hydroxymethyl)ethoxy]methyl)guanine in human diploid fibroblasts infected with human cytomegalovirus. Proc Natl Acad Sci U S A. 1985 Apr;82(8):2473–2477. doi: 10.1073/pnas.82.8.2473. [DOI] [PMC free article] [PubMed] [Google Scholar]
  4. Chatis P. A., Miller C. H., Schrager L. E., Crumpacker C. S. Successful treatment with foscarnet of an acyclovir-resistant mucocutaneous infection with herpes simplex virus in a patient with acquired immunodeficiency syndrome. N Engl J Med. 1989 Feb 2;320(5):297–300. doi: 10.1056/NEJM198902023200507. [DOI] [PubMed] [Google Scholar]
  5. Cheng Y. C., Dutschman G., Fox J. J., Watanabe K. A., Machida H. Differential activity of potential antiviral nucleoside analogs on herpes simplex virus-induced and human cellular thymidine kinases. Antimicrob Agents Chemother. 1981 Sep;20(3):420–423. doi: 10.1128/aac.20.3.420. [DOI] [PMC free article] [PubMed] [Google Scholar]
  6. Colacino J. M., Lopez C. Antiviral activity of 2'-deoxy-2'-fluoro-beta-D-arabinofuranosyl-5-iodocytosine against human cytomegalovirus in human skin fibroblasts. Antimicrob Agents Chemother. 1985 Aug;28(2):252–258. doi: 10.1128/aac.28.2.252. [DOI] [PMC free article] [PubMed] [Google Scholar]
  7. Collins P., Larder B. A., Oliver N. M., Kemp S., Smith I. W., Darby G. Characterization of a DNA polymerase mutant of herpes simplex virus from a severely immunocompromised patient receiving acyclovir. J Gen Virol. 1989 Feb;70(Pt 2):375–382. doi: 10.1099/0022-1317-70-2-375. [DOI] [PubMed] [Google Scholar]
  8. Dankner W. M., Scholl D., Stanat S. C., Martin M., Sonke R. L., Spector S. A. Rapid antiviral DNA-DNA hybridization assay for human cytomegalovirus. J Virol Methods. 1990 Jun;28(3):293–298. doi: 10.1016/0166-0934(90)90122-v. [DOI] [PubMed] [Google Scholar]
  9. Drew W. L., Buhles W., Erlich K. S. Herpesvirus infections (cytomegalovirus, herpes simplex virus, varicella-zoster virus). How to use ganciclovir (DHPG) and acyclovir. Infect Dis Clin North Am. 1988 Jun;2(2):495–509. [PubMed] [Google Scholar]
  10. Drew W. L., Miner R. C., Busch D. F., Follansbee S. E., Gullett J., Mehalko S. G., Gordon S. M., Owen W. F., Jr, Matthews T. R., Buhles W. C. Prevalence of resistance in patients receiving ganciclovir for serious cytomegalovirus infection. J Infect Dis. 1991 Apr;163(4):716–719. doi: 10.1093/infdis/163.4.716. [DOI] [PubMed] [Google Scholar]
  11. Drew W. L., Sweet E. S., Miner R. C., Mocarski E. S. Multiple infections by cytomegalovirus in patients with acquired immunodeficiency syndrome: documentation by Southern blot hybridization. J Infect Dis. 1984 Dec;150(6):952–953. doi: 10.1093/infdis/150.6.952. [DOI] [PubMed] [Google Scholar]
  12. Erice A., Chou S., Biron K. K., Stanat S. C., Balfour H. H., Jr, Jordan M. C. Progressive disease due to ganciclovir-resistant cytomegalovirus in immunocompromised patients. N Engl J Med. 1989 Feb 2;320(5):289–293. doi: 10.1056/NEJM198902023200505. [DOI] [PubMed] [Google Scholar]
  13. Estes J. E., Huang E. S. Stimulation of cellular thymidine kinases by human cytomegalovirus. J Virol. 1977 Oct;24(1):13–21. doi: 10.1128/jvi.24.1.13-21.1977. [DOI] [PMC free article] [PubMed] [Google Scholar]
  14. Fyfe J. A., McKee S. A., Keller P. M. Altered thymidine-thymidylate kinases from strains of herpes simplex virus with modified drug sensitivities to acyclovir and (E)-5-(2-bromovinyl)-2'-deoxyuridine. Mol Pharmacol. 1983 Sep;24(2):316–323. [PubMed] [Google Scholar]
  15. Gadler H. Nucleic acid hybridization for measurement of effects of antiviral compounds on human cytomegalovirus DNA replication. Antimicrob Agents Chemother. 1983 Sep;24(3):370–374. doi: 10.1128/aac.24.3.370. [DOI] [PMC free article] [PubMed] [Google Scholar]
  16. Garrett A. J., Warren D. E. A simple technique for endonuclease mapping of cytomegaloviruses. J Virol Methods. 1985 Mar;10(3):187–194. doi: 10.1016/0166-0934(85)90059-x. [DOI] [PubMed] [Google Scholar]
  17. Gibbs J. S., Chiou H. C., Bastow K. F., Cheng Y. C., Coen D. M. Identification of amino acids in herpes simplex virus DNA polymerase involved in substrate and drug recognition. Proc Natl Acad Sci U S A. 1988 Sep;85(18):6672–6676. doi: 10.1073/pnas.85.18.6672. [DOI] [PMC free article] [PubMed] [Google Scholar]
  18. Huang E. S. Human cytomegalovirus. III. Virus-induced DNA polymerase. J Virol. 1975 Aug;16(2):298–310. doi: 10.1128/jvi.16.2.298-310.1975. [DOI] [PMC free article] [PubMed] [Google Scholar]
  19. Hurley M. C., Lin B., Fox I. H. Regulation of deoxyadenosine and nucleoside analog phosphorylation by human placental adenosine kinase. J Biol Chem. 1985 Dec 15;260(29):15675–15681. [PubMed] [Google Scholar]
  20. Jacobson M. A., Mills J. Serious cytomegalovirus disease in the acquired immunodeficiency syndrome (AIDS). Clinical findings, diagnosis, and treatment. Ann Intern Med. 1988 Apr;108(4):585–594. doi: 10.7326/0003-4819-108-4-585. [DOI] [PubMed] [Google Scholar]
  21. Jacobson M. A., O'Donnell J. J., Mills J. Foscarnet treatment of cytomegalovirus retinitis in patients with the acquired immunodeficiency syndrome. Antimicrob Agents Chemother. 1989 May;33(5):736–741. doi: 10.1128/aac.33.5.736. [DOI] [PMC free article] [PubMed] [Google Scholar]
  22. Keller P. M., McKee S. A., Fyfe J. A. Cytoplasmic 5'-nucleotidase catalyzes acyclovir phosphorylation. J Biol Chem. 1985 Jul 25;260(15):8664–8667. [PubMed] [Google Scholar]
  23. Klintmalm G., Lönnqvist B., Oberg B., Gahrton G., Lernestedt J. O., Lundgren G., Ringdén O., Robert K. H., Wahren B., Groth C. G. Intravenous foscarnet for the treatment of severe cytomegalovirus infection in allograft recipients. Scand J Infect Dis. 1985;17(2):157–163. doi: 10.3109/inf.1985.17.issue-2.06. [DOI] [PubMed] [Google Scholar]
  24. Knopf C. W., Weisshart K. The herpes simplex virus DNA polymerase: analysis of the functional domains. Biochim Biophys Acta. 1988 Dec 20;951(2-3):298–314. doi: 10.1016/0167-4781(88)90100-5. [DOI] [PubMed] [Google Scholar]
  25. Krauss S. W., Linn S. Fidelity of fractionated deoxyribonucleic acid polymerases from human placenta. Biochemistry. 1980 Jan 8;19(1):220–228. doi: 10.1021/bi00542a033. [DOI] [PubMed] [Google Scholar]
  26. Krenitsky T. A., Tuttle J. V., Koszalka G. W., Chen I. S., Beacham L. M., 3rd, Rideout J. L., Elion G. B. Deoxycytidine kinase from calf thymus. Substrate and inhibitor specificity. J Biol Chem. 1976 Jul 10;251(13):4055–4061. [PubMed] [Google Scholar]
  27. Larder B. A., Kemp S. D., Darby G. Related functional domains in virus DNA polymerases. EMBO J. 1987 Jan;6(1):169–175. doi: 10.1002/j.1460-2075.1987.tb04735.x. [DOI] [PMC free article] [PubMed] [Google Scholar]
  28. Macher A. M., Reichert C. M., Straus S. E., Longo D. L., Parrillo J., Lane H. C., Fauci A. S., Rook A. H., Manischewitz J. F., Quinnan G. V., Jr Death in the AIDS patient: role of cytomegalovirus. N Engl J Med. 1983 Dec 8;309(23):1454–1454. doi: 10.1056/NEJM198312083092312. [DOI] [PubMed] [Google Scholar]
  29. Mar E. C., Chiou J. F., Cheng Y. C., Huang E. S. Inhibition of cellular DNA polymerase alpha and human cytomegalovirus-induced DNA polymerase by the triphosphates of 9-(2-hydroxyethoxymethyl)guanine and 9-(1,3-dihydroxy-2-propoxymethyl)guanine. J Virol. 1985 Mar;53(3):776–780. doi: 10.1128/jvi.53.3.776-780.1985. [DOI] [PMC free article] [PubMed] [Google Scholar]
  30. Meyers J. D., Flournoy N., Thomas E. D. Nonbacterial pneumonia after allogeneic marrow transplantation: a review of ten years' experience. Rev Infect Dis. 1982 Nov-Dec;4(6):1119–1132. doi: 10.1093/clinids/4.6.1119. [DOI] [PubMed] [Google Scholar]
  31. Pau A. K., Pitrak D. L. Management of cytomegalovirus infection in patients with acquired immunodeficiency syndrome. Clin Pharm. 1990 Aug;9(8):613–631. [PubMed] [Google Scholar]
  32. Peterson P. K., Balfour H. H., Jr, Marker S. C., Fryd D. S., Howard R. J., Simmons R. L. Cytomegalovirus disease in renal allograft recipients: a prospective study of the clinical features, risk factors and impact on renal transplantation. Medicine (Baltimore) 1980 Jul;59(4):283–300. [PubMed] [Google Scholar]
  33. Quinnan G. V., Jr, Masur H., Rook A. H., Armstrong G., Frederick W. R., Epstein J., Manischewitz J. F., Macher A. M., Jackson L., Ames J. Herpesvirus infections in the acquired immune deficiency syndrome. JAMA. 1984 Jul 6;252(1):72–77. [PubMed] [Google Scholar]
  34. Ringdén O., Lönnqvist B., Paulin T., Ahlmén J., Klintmalm G., Wahren B., Lernestedt J. O. Pharmacokinetics, safety and preliminary clinical experiences using foscarnet in the treatment of cytomegalovirus infections in bone marrow and renal transplant recipients. J Antimicrob Chemother. 1986 Mar;17(3):373–387. doi: 10.1093/jac/17.3.373. [DOI] [PubMed] [Google Scholar]
  35. Sacks S. L., Wanklin R. J., Reece D. E., Hicks K. A., Tyler K. L., Coen D. M. Progressive esophagitis from acyclovir-resistant herpes simplex. Clinical roles for DNA polymerase mutants and viral heterogeneity? Ann Intern Med. 1989 Dec 1;111(11):893–899. doi: 10.7326/0003-4819-111-11-893. [DOI] [PubMed] [Google Scholar]
  36. Safrin S., Berger T. G., Gilson I., Wolfe P. R., Wofsy C. B., Mills J., Biron K. K. Foscarnet therapy in five patients with AIDS and acyclovir-resistant varicella-zoster virus infection. Ann Intern Med. 1991 Jul 1;115(1):19–21. doi: 10.7326/0003-4819-115-1-19. [DOI] [PubMed] [Google Scholar]
  37. Smee D. F. Interaction of 9-(1,3-dihydroxy-2-propoxymethyl)guanine with cytosol and mitochondrial deoxyguanosine kinases: possible role in anti-cytomegalovirus activity. Mol Cell Biochem. 1985 Nov;69(1):75–81. doi: 10.1007/BF00225929. [DOI] [PubMed] [Google Scholar]
  38. St Clair M. H., Furman P. A., Lubbers C. M., Elion G. B. Inhibition of cellular alpha and virally induced deoxyribonucleic acid polymerases by the triphosphate of acyclovir. Antimicrob Agents Chemother. 1980 Nov;18(5):741–745. doi: 10.1128/aac.18.5.741. [DOI] [PMC free article] [PubMed] [Google Scholar]
  39. Walmsley S. L., Chew E., Read S. E., Vellend H., Salit I., Rachlis A., Fanning M. M. Treatment of cytomegalovirus retinitis with trisodium phosphonoformate hexahydrate (Foscarnet). J Infect Dis. 1988 Mar;157(3):569–572. doi: 10.1093/infdis/157.3.569. [DOI] [PubMed] [Google Scholar]
  40. Weiner R. S., Bortin M. M., Gale R. P., Gluckman E., Kay H. E., Kolb H. J., Hartz A. J., Rimm A. A. Interstitial pneumonitis after bone marrow transplantation. Assessment of risk factors. Ann Intern Med. 1986 Feb;104(2):168–175. doi: 10.7326/0003-4819-104-2-168. [DOI] [PubMed] [Google Scholar]
  41. Winston D. J., Gale R. P., Meyer D. V., Young L. S. Infectious complications of human bone marrow transplantation. Medicine (Baltimore) 1979 Jan;58(1):1–31. doi: 10.1097/00005792-197901000-00001. [DOI] [PubMed] [Google Scholar]

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