Resistance of Herpes Viruses to Nucleoside Analogues — Mechanisms and Clinical Importance
The study of resistance to antiviral drugs provides an important method to determine mechanisms of drug action. A mutation in the gene for a viral enzyme which enables a virus to replicate in the presence of the active form of a drug provides evidence that the mechanism of action involves the viral gene product. In the study of DNA replication, Kornberg observed that mutants possessing temperature sensitive and drug resistant mutations were the most important classes of mutants for defining precise mechanisms of DNA replication (1). A key feature in showing that the current class of antiviral drugs are specific for herpes viruses has been related to the fact that they readily select for resistance in herpes viruses and the resistance markers can be mapped to viral specific functions. Another important reason to study resistance of herpes viruses to antiviral drugs is that resistance can occur in the course of clinical treatment of herpes virus infections and development of resistance may account for failure of antiviral therapy. Resistant mutants of herpes viruses may also possess altered pathogenetic properties and produce unusual disease manifestations. In this review, the mechanisms of resistance to various nucleoside analogues will be outlined, and the cases where clinical resistance has been observed will be summarized.
KeywordsThymidine Kinase Nucleoside Analogue Antiviral Drug Herpes Virus Genital Herpes
Unable to display preview. Download preview PDF.
- 1.Kornberg, A. In: DNA Replication. Chapter 13. Freeman, New York, 1980.Google Scholar
- 4.Terse, D., Cheng, Y.-C, Furman, P.A., St. Clair, K.R. and Elion, G.B. J. Biol. Chem. 256: 11447–11451, 1981.Google Scholar
- 41.Reinhold, R. et al. J. Virol. 61, in press, 1987.Google Scholar
- 47.Chatis, P., Germershausen, J., Field, A.K. and Crumpacker, C.S. Abstract of the 11th International Herpes Workshop, 1985.Google Scholar
- 48.Schinazi, R.F., del Bene, V., Scctt, R.T. and Dudley-Thorpe, J.-B. J. Antimicrob. Agents Chemother. 18 (Suppl. B): 127–134, 1986.Google Scholar
- 49.Svennerholm, E., Vahlne, A., Löwhagen, G.B., Widell, A. and Lycke, E. Scand. J. Infect. Dis., Suppl. 47: 149–154, 1985.Google Scholar
- 57.Marlowe, S.I., Kowalsky, P.A., Douglas, J., Corey, C. and Crumpacker, C.S. Abstract of the 24th Interscience Conference on Antimicrobial Agents and Chemotherapy, 1984.Google Scholar
- 58.Nusinoff Lehrman, S., Douglas, J.M., Corey, L. and Barry, D.W. Ann. Intern. Med. 104: 786–790, 1986.Google Scholar