Abstract
Drug-resistant human Cytomegalovirus (HCMV) strains were selected in human embryonic lung (HEL) fibroblasts under pressure of the (S)-3-hydroxy-2-phosphonylmethoxypropyl (HPMP) derivatives of cytosine (HPMPC) and adenine (HPMPA), the 2-phosphonylmethoxyethyl (PME) derivative of 2,6-diaminopurine (PMEDAP), ganciclovir (GCV), acyclovir (ACV), and foscarnet (PFA). Drug susceptibility profiles of the different drug-resistant (i.e., GCVr, HPMPCr, HPMPAr, PFAr, ACVr, and PMEDAPr) strains were determined in HEL cells. A considerable degree of cross-resistance against GCV, HPMPC, and HPMPA occurred with the GCVr, HPMPCr, and HPMPAr strains. No changes in susceptibility to 9-(2-phosphonylmethoxyethyl)adenine (PMEA), PMEDAP, ACV, or PFA were detected for the HPMPCr, HPMPAr, and GCVr strains when compared to the wild-type virus. On the other hand, a significant degree of cross-resistance was noted with the PMEDAPr, PFAr, and ACVr strains against PMEA, PMEDAP, PFA, and ACV. No differences in susceptibility to HPMPC, HPMPA and GCV were observed for the ACVr, PFAr, and PMEDAPr strains relative to the wild type. The drug susceptibility profiles of the different resistant strains point to a common mechanism of HCMV resistance to PFA and the PME derivatives that is different from the mechanism of HCMV resistance to the HPMP derivatives.
Similar content being viewed by others
References
Laskin OL, Stahl-Baylis CM, Kaiman CM, Rosecan LR: Use of ganciclovir to treat serious cytomegalovirus infections in patients with AIDS. Journal of Infectious Diseases 1987, 155: 323–327.
Mills J, Jacobson MA, O'Donnell JJ, Cederberg D, Holland GN: Treatment of cytomegalovirus retinitis in patients with AIDS. Reviews of Infectious Diseases 1988, 10, Supplement 3: 522–531.
Drew WL, Miner RC, Busch DF, Follansbee SE, Gullett J, Mehalko SG, Gordon SM, Owen WF Jr, Matthews TR, Buhles WC, DeArmond B: Prevalence of resistance in patients receiving ganciclovir for serious cytomegalovirus infection. Journal of Infectious Diseases 1991, 163: 716–719.
Erice A, Chou S, Biron KK, Stanat SC, Balfour HH Jr, Jordan MC: Progressive disease due to ganciclovir-resistant cytomegalovirus in immunocompromised patients. New England Journal of Medicine 1989, 320: 289–293.
Stanat SC, Reardon JE, Erice A, Jordan MC, Drew WL, Biron KK: Ganciclovir-resistant cytomegalovirus clinical isolates: mode of resistance to ganciclovir. Antimicrobial Agents and Chemotherapy 1991, 35: 2191–2197.
Jacobson MA, Drew WL, Feinberg J, O'Donnell JJ, Whitmore PV, Miner RD, Parenti D: Foscarnet therapy for ganciclovir-resistant cytomegalovirus retinitis in patients with AIDS. Journal of Infectious Diseases 1991, 163: 1348–1351.
Palestine AG, Polis MA, De Smet MD, Baird BF, Falloon J, Kovac JA: A randomized, controlled trial of foscarnet in the treatment of cytomegalovirus retinitis in patients with AIDS. Annals of Internal Medicine 1991, 115: 665–673.
Sullivan V, Coen DM: Isolation of foscarnet-resistant human cytomegalovirus patterns of resistance and sensitivity to other antiviral drugs. Journal of Infectious Diseases 1991, 164: 781–784.
Knox KK, Drobyski WR, Carrigan DR: Cytomegalovirus isolate resistant to ganciclovir and foscarnet from a marrow transplant patient. Lancet 1991, 337: 1292–1293.
De Clercq E: Therapeutic potential of HPMPC as an antiviral drug. Reviews in Medical Virology 1993, 3: 85–96.
Snoeck R, Sakuma T, De Clercq E, Rosenberg I, Holy A: (S)-1(3-hydroxy-2-phosphonylmethoxyprophyl)cytosine, a potent and selective inhibitor of human cytomegalovirus replication. Antimicrobial Agents and Chemotherapy 1988, 32: 1839–1844.
Neyts J, Snoeck R, Schols D, Baizarini J, De Clercq E: Selective inhibition of human cytomegalovirus DNA synthesis by (S)-1-(3-hydroxy-2-phosphonylmethoxy-propyl)cytosine [(S)-HPMPC] and 9-(1,3-dihydroxy-2-propoxymethyl)guanine (DHPG). Virology 1990, 179: 41–50.
Neyts J, Baizarini J, Naesens L, De Clercq E: Efficacy of (S)-1-(3-hydroxy-2-phosphonylmethoxypropyl)cytosine and 9-(1,3-dihydroxy-2-propoxymethyl)guanine for the treatment of murine cytomegalovirus infection in severe combined immunodeficiency mice. Journal of Medical Virology 1992, 37: 67–71.
Drew WL, Lalezari JP, Glutzer E, Lynch T, Flaherty J, Martin JC, Fisher PE, Jaffe HS: The safety, pharmacokinetics, and anti-CMV activity of weekly HPMPC in HIV positive patients excreting CMV. In: Michelson S, Plotkin S (ed): Multidisciplinary approach to understanding cytomegalovirus disease. Excerpta Medica, Elsevier, Amsterdam, 1993, p. 287–292.
Andrei G, Snoeck R, Schols D, Goubau P, Desmyter J, De Clercq E: Comparative activity of selected antiviral compounds against clinical isolates of human cytomegalovirus. European Journal of Clinical Microbiology & Infectious Diseases 1991, 10: 1026–1033.
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: 160–164.
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.
Sullivan V, Biron KK, Talarico C, Stanat SC, Davis M, Pozzi LM, Coen DM: A point mutation in the human cytomegalovirus DNA polymerase gene confers resistance to ganciclovir and phosphonylmethoxyalkyl derivatives. Antimicrobial Agents and Chemotherapy 1993, 37: 19–25.
Lurain NS, Thompson KD, Holmes EW, Read GS: Point mutations in the DNA polymerase gene of human cytomegalovirus that result in resistance to antiviral agents. Journal of Virology 1992, 66: 7146–7152.
Lurain NS, Spafford LS, Thompson KD: Mutation in the UL97 open reading frame of human cytomegalovirus strains resistant to ganciclovir. Journal of Virology 1994, 68: 4427–4431.
Baldanti F, Silini E, Sarasini A, Talarico CL, Stanat SC, Biron KK, Furione M, Bono F, Palu G, Gerna G: A three-nucleotide deletion in the UL97 open reading frame is responsible for the ganciclovir resistance of a human cytomegalovirus clinical isolate. Journal of Virology 1995, 69: 796–800.
Andrei G, Snoeck R, De Clercq E: Susceptibilities of several drug-resistant herpes simplex virus type 1 strains to alternative antiviral compounds. Antimicrobial Agents and Chemotherapy 1995, 39: 1632–1635.
Coen DM: General aspects of virus drug resistance with special reference to herpes simplex virus. Journal of Antimicrobial Chemotherapy 1986, 18, Supplement B: 1–10.
Biron KK, Fyfe JA, Stanat SC, Leslie LK, Sorrell JB, Lambe CU, Coen DM: 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. Proceedings of the National Academy of Sciences of the USA 1986, 83: 8769–8773.
Tatarowicz WA, Lurain NS, Thompson KD: A ganciclovir-resistant clinical isolate of human cytomegalovirus exhibiting cross-resistance to other DNA polymerase inhibitors. Journal of Infectious Diseases 1992, 166: 904–907.
Author information
Authors and Affiliations
Rights and permissions
About this article
Cite this article
Snoeck, R., Andrei, G. & De Clercq, E. Patterns of resistance and sensitivity to antiviral compounds of drug-resistant strains of human cytomegalovirus selected in vitro. Eur. J. Clin. Microbiol. Infect. Dis. 15, 574–579 (1996). https://doi.org/10.1007/BF01709366
Issue Date:
DOI: https://doi.org/10.1007/BF01709366