Heterogeneity of a Herpes Simplex Virus Clinical Isolate Exhibiting Resistance to Acyclovir and Foscarnet

  • Emanuela Pelosi
  • Karen A. Hicks
  • Stephen L. Sacks
  • Donald M. Coen
Part of the Advances in Experimental Medicine and Biology book series (AEMB, volume 312)


Resistance of herpes simplex virus to acyclovir is a problem of growing clinical importance. Acyclovir-resistance can be due either to mutations in the viral thymidine kinase gene or in the viral DNA polymerase gene. Although clinical resistance has most frequently been associated with thymidine kinase alterations, heterogeneity in clinical isolates has not been addressed frequently. The potential for such heterogeneity has been emphasized by a report describing a pathogenic clinical isolate containing within its population at least one thymidine kinase-proficient DNA polymerase mutant as well as mutants exhibiting thymidine kinase-deficiency (Sacks, et al., 1989). We provide here additional characterization of this isolate and speculations regarding its significance.


Herpes Simplex Virus Type Thymidine Kinase Herpes Simplex Virus Thymidine Kinase Thymidine Kinase Activity Plaque Reduction Assay 
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  1. Chatis, P.A., Miller, C.H., Schrager, L.E., and Crumpacker, C.S., 1989, Successful treatment with foscarnet of an acyclovir-resistant mucocutaneous infection with herpes simples virus in a patient with acquired immunodeficiency syndrome, N. Engl. J. Med. 320:297–300.CrossRefPubMedGoogle Scholar
  2. Coen, D.M., 1991, The implications of resistance to antiviral agents for herpesvirus drug targets and drug therapy, Antiviral Res., 15:287–300.CrossRefPubMedGoogle Scholar
  3. Coen, D.M., Furman, P.A., Aschman, D.P., and Schaffer, P.A., 1983, Mutations in the herpes simplex virus DNA polymerase gene conferring hypersensitivity to aphidicolin, Nucleic Acids Res. 11:5287–5297.CrossRefPubMedGoogle Scholar
  4. Coen, D.M., Fleming, H.E., Jr., Leslie, L.K., and Retondo, M.J., 1985, Sensitivity of arabinosyladenine-resistant mutants of herpes simplex virus to other antiviral drugs and mapping of drug hypersensitivity mutations to the DNA polymerase locus, J. Virol. 53:477–488.PubMedGoogle Scholar
  5. Coen, D.M., and Schaffer, P.A., 1980, Two distinct loci confer resistance to acycloguanosine in herpes simplex virus type 1, Proc. Natl. Acad. Sci. USA 77:2265–2269.CrossRefPubMedGoogle Scholar
  6. Collins, P., Larder, B.A., Oliver, N.M., Kemp, S., Smith, I.W., and Darby, G., 1989, Characterization of a DNA polymerase mutant of herpes simplex virus from a severely immunocompromised patient receiving acyclovir, J. Gen. Virol. 70:375–382.CrossRefPubMedGoogle Scholar
  7. Ellis, M.N., Waters, R., Hill, E.L., Lober, D.C., Selleseth, D.W., and Barry, D.W., 1989, Orofacial infection of athymic mice with defined mixtures of acyclovirsusceptible and acyclovir-resistant herpes simplex virus type 1, Antimicrob. Agents Chemother. Google Scholar
  8. Englund, J.A., Zimmerman, M.E., Swierkosz, E.M., Goodman, J.L., Scholl, D.R., and Balfour, H.H., Jr., 1990, Herpes simplex virus resistant to acyclovir: a study in a tertiary care center, Ann. Intern. Med. 112:416–422.PubMedGoogle Scholar
  9. Erlich, K.S., Mills, J., Chatis, P., Mertz, G.J., Busch, D.F., Follansbee, S.E., Grant, R.M., and Crumpacker, C.S., 1989, Acyclovir-resistant herpes simplex virus infections in patients with the acquired immunodeficiency syndrome, N. Engl. J. Med. 320:293–296.CrossRefPubMedGoogle Scholar
  10. Field, H.J., 1982, Development of clinical resistance to acyclovir in herpes simplex virus-infected mice receiving oral therapy, Antimicrob. Angent Chemother. 21:744–752.CrossRefGoogle Scholar
  11. Field, H.J., and Lay, E., 1984, Characterization of latent infections in mice inoculated with herpes simplex virus which is clinically resistant to acyclovir, Antiviral Res. 4:43–52.CrossRefPubMedGoogle Scholar
  12. Furman, P.A., St. Clair, M.H., Fyfe, J.A., Rideout, J.L., Keller, P.M., and Elion, G.B., 1979, Inhibition of herpes simplex virus induced DNA polymerase activity and viral DNA replication by 9-(2-hydroxyethoxymethyl)guanine and its triphosphate, J. Virol. 32:72–77.PubMedGoogle Scholar
  13. Fyfe, J.A., Keller, P.M., Furman, P A, Miller, R.L., and Elion, G.B., 1978, Thymidine kinase from herpes simplex virus phosphorylates the new antiviral compound 9- (2-hydroxyethoxymethyl)guanine, J. Biol. Chem. 253:8721–8727.PubMedGoogle Scholar
  14. Hicks, K.A., and Coen, D.M., unpublished results.Google Scholar
  15. Krokan, H., Schaffer, P., and DePamphilis, M., 1979, Involvement of eucaryotic deoxyribonucleic acid polymerases alpha and gamma in replication of cellular and viral deoxyribonucleic acid, Biochemistry 18:4431–4443.CrossRefPubMedGoogle Scholar
  16. Larder, B.A., and Darby, G., Virus drug resistance: mechanisms and consequences, Antiviral Res. 4:1–42.Google Scholar
  17. Norris, S.A., Kessler, H.A., and Fife, K.H., 1988, Severe progressive herpetic whitlow caused by an acyclovir-resistant virus in a patient with AIDS, J. Infect. Dis. 157:209–210.CrossRefPubMedGoogle Scholar
  18. Parker, A.C., Craig, J.I., Collins, P., Oliver, N., and Smith, I., 1987, Acyclovir-resistant herpes simplex virus infection due to altered DNA polymerase, Lancet 2:1461.CrossRefPubMedGoogle Scholar
  19. Pelosi, E., Tyler, K.L., Hwang, C.B.C., and Coen, D.M., manuscript in preparation.Google Scholar
  20. Sacks, S.L., Wanklin, R.J., Reece, D.E., Hicks, K.A., Tyler, K.L., and Coen, D.M., 1989, Progressive esophagitis from acyclovir-resistant herpes simplex: clinical roles for DNA polymerase mutants and viral heterogeneity?, Ann. Intern. Med. 111:893–899.PubMedGoogle Scholar
  21. Sedarati, F., Javier, R.T., and Stevens, J.G., 1988, Pathogenesis of a lethal mixed infection in mice with two nonneuroinvasive herpes simplex virus strains, J. Virol. 62:3037–3039.PubMedGoogle Scholar
  22. Weller, S.K., Aschman, D.P., Sacks, W.R., Coen, D.M., and Schaffer, P.A., 1983, Genetic analysis of temperature-sensitive mutants of HSV-1: the combined use of complementation and physical mapping for cistron assignment, Virology 130:290–305.CrossRefPubMedGoogle Scholar

Copyright information

© Springer Science+Business Media New York 1992

Authors and Affiliations

  • Emanuela Pelosi
    • 1
  • Karen A. Hicks
    • 1
  • Stephen L. Sacks
    • 2
  • Donald M. Coen
    • 1
  1. 1.Department of Biological Chemistry and Molecular PharmacologyHarvard Medical SchoolBostonUSA
  2. 2.Division of Infectious DiseasesUniversity of British ColumbiaVancouverCanada

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