Cytomegalovirus: Genetics of Drug Resistance

  • Karen K. Biron
Part of the Advances in Experimental Medicine and Biology book series (AEMB, volume 394)


Human cytomegalovirus (CMV) shares the characteristic ability of other herpesviruses to establish persistence or life-long latency following primary infection, and to reactivate subsequently as host cell-mediated immunity diminishes.1 However, CMV has clearly evolved unique strategies for intracellular replication, pathogenesis and persistence in the host. The regulatory mechanisms and biological sites for viral persistence and reactivation of CMV are poorly understood, but clearly they do not involve the neurotropic pathways employed by herpes simplex virus (HSV) or varicella zoster virus (VZV). CMV infections in immunocompromised patients, especially bone marrow and organ transplant recipients and patients with AIDS, are a major cause of morbidity and mortality. These infections most commonly are reactivations of prior latent infection. Reactivation likely begins with a viremic phase, during which virus can be detected in blood mononuclear cells, followed by symptoms and signs of organ involvement, such as retinitis, pneumonitis, or colitis. Individuals may be infected with multiple strains of CMV, which can reactivate sequentially or simultaneously.2, 3 Different strains or populations of virus may be present at different body sites, with variable accessibility to individual antiviral drugs. Currently approved therapies for the suppression and treatment of CMV include ganciclovir (GCV), foscarnet (PFA), and acyclovir (ACV). Acyclovir is less active in treatment of established CMV infections, but it can reduce the reactivation of latent infection, and resulting CMV disease, in bone marrow and solid organ transplant patients. Several factors point to the likelihood of drug-resistant strains of CMV developing Most disease occurs in immunocompromised patients, who have a high viral load and for whom control of the infection depends almost solely on antiviral therapy. In addition, chronic therapy is frequently necessary


Human Cytomegalovirus UL97 Gene Solid Organ Transplant Patient Phosphonoacetic Acid UL97 Mutation 
These keywords were added by machine and not by the authors. This process is experimental and the keywords may be updated as the learning algorithm improves.


Unable to display preview. Download preview PDF.

Unable to display preview. Download preview PDF.


  1. 1.
    Mocarski ES Jr. Cytomegalovirus biology and replication. The Human Herpesviruses ed. B Roizman, RJ Whitley, C Lopez, Raven Press Ltd., NY, 1993.Google Scholar
  2. 2.
    Drew WL, Sweet ES, Miner RC, Mocarski ES. Multiple infections by cytomegalovirus in patients with acquired immunodeficiency syndrome: Documentation by Southern Blot Hybridization. J Infect Dis 1984; 150: 952–953.PubMedCrossRefGoogle Scholar
  3. 3.
    Chou S. Differentiation of cytomegalovirus strains by restriction analysis of DNA sequences amplified from clinical specimens. J Virol 1990; 162: 738–742.Google Scholar
  4. 4.
    Drew WL, Miner RC, Busch DF, Follansbee SE, Gullett J, Mehalko SG, Gordon SM, Owen WF, Matthews TR, Bullies WC, Deamond B. Prevalence of resistance in patients receiving ganciclovir for serious cytomegalovirus infection. J Infect Dis 1991; 163: 716–719.PubMedCrossRefGoogle Scholar
  5. 5.
    Erice A, Chou S, Biron KK, Stanat SC, Balfour HH, Jordan MC. Progressive disease due to ganciclovirresistant cytomegalovirus in immunocompromised patients. N Engl J Med 1989; 320: 289–293.PubMedCrossRefGoogle Scholar
  6. 6.
    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. J Infect Dis 1991; 163: 1348–1351.PubMedCrossRefGoogle Scholar
  7. 7.
    Stanat SC, Reardon JE, Erice A, Jordan MC, Drew WL, Biron KK. Ganciclovir-resistant cytomegalovirus clinical isolates: Mode of resistance of ganciclovir. Antimicrob Agents Chemother 1991; 35: 2191–2197.PubMedCrossRefGoogle Scholar
  8. 8.
    Plotkin SA, Drew WL, Felsenstein D, Hirsch MS. Sensitivity of clinical isolates of human cytomegalovirus to 9(-1,3,dihydroxy-2-propoxymethyl) guanine. J Infect Dis 1985; 152: 833–834.PubMedCrossRefGoogle Scholar
  9. 9.
    Drew WL, Miner RC, Saleh E. Antiviral susceptibility testing of cytomegalovirus: criteria for detecting resistance to antivirals. Clin Diag Vir 1993; 1: 179–185.CrossRefGoogle Scholar
  10. 10.
    Gerna G, Baldanti F, Zavattoni M, Sarasini A, Percivalle E, Revello MG. Monitoring of ganciclovir sensitivity of human cytomegalovirus strains coinfecting blood of an AIDS patient by an immediate-early antigen plaque assay. Antivir Res 1992; 19: 333–345.PubMedCrossRefGoogle Scholar
  11. 11.
    Sullivan V, Talarico CL, Stantat SC, Davis M, Coen DM, Biron KK. A protein kinase homologue controls phosphorylation of ganciclovir in human cytomegalovirus-infected cells. Nature 1992, 358: 16 2164.Google Scholar
  12. 12.
    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.PubMedCrossRefGoogle Scholar
  13. 13.
    Mar EC, Chiou JF, Cheng YC, Huang ES. Inhibition of cellular DNA polymerase a and human cytomegalovirus-induced DNA polymerase by the triphosphates of 9-(2-hydroxy-ethoxymethyl)guanine and 9-(1,3-dihydroxy-2-propoxy-methyl)guanine. J Virol 1985; 53: 776–780.PubMedGoogle Scholar
  14. 14.
    Neyts J, Snoeck R, Schols D, Balzarini J, DeClercq E. Selective inhibition of human cytomegalovirus DNA synthesis by (S)-1-(3-hydroxy-2-phosphonylmethoxypropyl)cytosine ((S)-HPMPCI and 9-(1,3dihyroxy-2-propoxymethyl)guanine (DHPG). Virology 1990; 179: 41–50.PubMedCrossRefGoogle Scholar
  15. 15.
    Field, AK, Biron KK. “The end of innocence” revisited: Resistance of herpesviruses to antiviral drugs. Clin Microbiol Reviews 1994; 7: 1–13.Google Scholar
  16. 16.
    Larder BA, Kemp SD, Darby G. Related functional domains in virus DNA polymerases. EMBO J 1987; 6: 169–175.PubMedGoogle Scholar
  17. 17.
    Coen DM. The implications of resistance to antiviral agents for herpesvirus drug targets and drug therapy. Antiviral Res. 15: 287–300.Google Scholar
  18. 18.
    Biron KK, Stanat SC, Fyfe JA, Roberts G, Ostrove J, Short S, Gaillard R. Genetic heterogeneity in a drug-resistant VZV isolate recovered from an AIDS patient. 14th International Herpesvirus Workshop, Nyborg, Denmark, August 1989;p. 248.Google Scholar
  19. 19.
    Gaillard R, Short S, Gaillard M, Stanat, S, Biron K. Sequence alterations in the DNA polymerase gençs of VZV strains selected for in vitro resistance to acyclovir or phosphonoacetic acid. 15th International Herpesvirus Workshop, Georgetown Univ., Washington, DC August 1990;p. 154.Google Scholar
  20. 20.
    Stanat SC, Talarico CL, Safrin S, Biron KK. Sequential varicella zoster virus isolates from an AIDS patient: Phenotypic and genetic evidence for evolution of drug resistance at the thymidine kinase and DNA polymerase loci. Antiviral Res 1992; 17: (Suppl 1), p. 51.Google Scholar
  21. 21.
    Sullivan V, Coen DM. Isolation of foscarnet-resistant human cytomegalovirus: patterns of resistance and sensitivity to other antiviral drugs. J Infect Dis 1991; 164: 781–784.PubMedCrossRefGoogle Scholar
  22. 22.
    D’Aquila RT, Summers WC. Isolation and characterization of phosphonoacetic acid-resistant mutants of human cytomegalovirus. J Virol 1987; 61: 1291–1295.PubMedGoogle Scholar
  23. 23.
    Tatarowicz WA, Lurain NS, Thompson KD. A ganciclovir-resistant clinical isolate of human cytomegalovirus exhibiting cross-resistance of other DNA polymerase inhibitors. J Infect Dis 1992; 166: 904–907.PubMedCrossRefGoogle Scholar
  24. 24.
    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. J Virol 1992; 66: 7146–7152.PubMedGoogle Scholar
  25. 25.
    Sullivan V, Biron KK, Talarico C, Stanat SC, Davis M, Possi LM, Coen DM. A point mutation in the human cytomegalovirus DNA polymerase gene confers resistance to ganciclovir and phosphonylmethozyalkyl derivatives. Antimicrob Agents Chemother 1993; 37: 19–25.PubMedCrossRefGoogle Scholar
  26. 26.
    Lurain NS, Penland LK, Thompson KD. Ganciclovir-resistant DNA polymerase mutants isolated from an HCMV clinical specimen. The 19th International Herpesvirus Workshop 1994; Abstract 211.Google Scholar
  27. 27.
    Knox, KK, Drobyski WR, Carrigan DR. Cytomegalovirus isolate resistant to ganciclovir and foscarnet from a marrow transplant patient. Lancet 1991; 337: 1292–1293.PubMedCrossRefGoogle Scholar
  28. 28.
    Leport C, Puget S, Pepin JM, et al. Cytomegalovirus resistant to foscamet: Clinicovirologic correlation in patient with human immunodeficiency virus. J Infect Dis 1993; 168: 1329–1330.PubMedCrossRefGoogle Scholar
  29. 28a.
    Birch, CJ, Tachedijian G, Doherty R, Hayes K, Gust I. Altered Sensitivity to Antiviral Drugs of Herpes Simplex Virus Isolates from a Patient with the Acquired Immunodeficiency Syndrome. J Infect Dis 1990; 162: 731–734.PubMedCrossRefGoogle Scholar
  30. 29.
    Chee MS, Lawrence GL, Harrell BG. Alpha-, beta-and gamma herpesviruses encode a putative phosphotransferase. J Gen Virol 1989; 70: 1151–1160.PubMedCrossRefGoogle Scholar
  31. 30.
    Hanks SK, Quinn AM, Hunter T. The protein kinase family: Conserved features and deduced phylogeny of the catalytic domains. Science 1988; 241: 42–52.PubMedCrossRefGoogle Scholar
  32. 31.
    Smith RF, Smith TF. Identification of new protein kinase-related genes in three herpesviruses, herpes simplex virus, varicella-zoster virus, and Epstein-Barr virus. J Virol 1989; 63: 450–455.PubMedGoogle Scholar
  33. 32.
    Coulter LJ, Moss HWM, Lang J, McGeoch DJ. A mutant of herpes simplex virus type 1 in which the UL13 protein kinase gene is disrupted. J Gen Virol 1993; 74: 387–395.PubMedCrossRefGoogle Scholar
  34. 33.
    Purves FC, Roizman. The UL13 gene of herpes simplex virus 1 encodes the functions for posttranslational processing associated with phosphorylation of the regulatory protein g22. Proc Natl Acad Sci USA 1992; 89: 7310–7314.PubMedCrossRefGoogle Scholar
  35. 34.
    Purves FC, Ogle WO, Roizman. Processing of the herpes simplex virus regulatory protein g22 mediated by the ÚL13 protein kinase determines the accumulation of a subset of g and g mRNAs and proteins in infected cells. Proc Natl Acad Sci USA 1993; 90: 6701–6705.PubMedCrossRefGoogle Scholar
  36. 35.
    Ng TI, Keenan L, Kinchington PR, Grose C. Phosphorylation of varicella-zoster virus open reading frame (ORF) 62 regulatory product by viral ORF 47-associated protein kinase. J Virol 1994; 68: 1350 1359.Google Scholar
  37. 36.
    Overton H, McMillan D, Hope L, Wong-Kai-In P. Production of host shutoff-defective mutants of herpes simplex virus type 1 by inactivation of the UL13 gene. Virol. 1994; 202: 97–106.CrossRefGoogle Scholar
  38. 37.
    Wolf DG, Spector SA. Central nervous system (CNS) infection with ganciclovir-resistant human cytomegalovirus (CMV) in AIDS patients determined by analysis of the UL97 gene in cerebrospinal fluid. Abstracts of the 34th ICAAC, University of California, San Diego, La Jolla, CA.Google Scholar
  39. 38.
    Chou S, Erice A, Jordan MC, Vercellotti GM, Michels KR, Talarico CL, Stanat SC. Biron KK. Analysis of the UL97 Phosphotransferasc coding sequence in clinical cytomegalovirus isolates and identification of mutations conferring ganciclovir resistance. J Infect Dis 1995; 171: 576–583.PubMedCrossRefGoogle Scholar
  40. 39.
    Lurain N, Spafford LE, Thompson KD. Mutation in the UL97 open reading frame of human cytomegalovirus strains resistant to ganciclovir. J Virol 1994; 68: 4427–4431.PubMedGoogle Scholar
  41. 40.
    Wolf DG, Smith IL, Lee DJ, Salunga RC, Spector SA. Molecular basis of human cytomegalovirus ganciclovir resistance: Analysis of the UL96 open reading frame in clinical isolates. Interscience Conference on Antimicrob Agents & Chemother, New Orleans, Louisiana, 1993; Abstract 1200.Google Scholar
  42. 41.
    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 ORF is responsible for the ganciclovir resistance of human cytomegalovirus clinical isolate. J Virol 1994; Submitted.Google Scholar
  43. 42.
    Hanson MH, Erice A, Talaico CL, Preheim LC, Biron KK, Stanat SC, Balfour H-I, Jr. Characterization of a novel mutation in the UL97 gene of a clinical cytomegalovirus (CMV) strain conferring resistance to ganciclovir (GCV). Abstracts of the 34th ICAAC, University’of Minnesota Medical School, MN; Burroughs Wellcome Co., NC and VA Medical Center, Omaha, NE.Google Scholar
  44. 43.
    Knighton DR, Zheng 1, Eyck LET, Xuong N-H, Taylor SS, Sowadski JM. Structure of a peptide inhibitor bound to the catalytic subunit of cyclic adenosine monophosphate-dependent protein kinase. Science 1991; 253: 414–420.PubMedCrossRefGoogle Scholar

Copyright information

© Springer Science+Business Media New York 1996

Authors and Affiliations

  • Karen K. Biron

There are no affiliations available

Personalised recommendations