Resistance of herpesviruses to antiviral drugs: clinical impacts and molecular mechanisms.
Nucleoside analogues such as acyclovir and ganciclovir have been the mainstay of therapy for alphaherpesviruses (herpes simplex virus (HSV) and varicella-zoster virus (VZV)) and cytomegalovirus (CMV) infections, respectively. Drug-resistant herpesviruses are found relatively frequently in the clinic, almost exclusively among severely immunocompromised patients receiving prolonged antiviral therapy. For instance, close to 10% of patients with AIDS receiving intravenous ganciclovir for 3 months excrete a drug-resistant CMV isolate in their blood or urine and this percentage increases with cumulative drug exposure. Many studies have reported that at least some of the drug-resistant herpesviruses retain their pathogenicity and can be associated with progressive or relapsing disease. Viral mutations conferring resistance to nucleoside analogues have been found in either the drug activating/phosphorylating genes (HSV or VZV thymidine kinase, CMV UL97 kinase) and/or in conserved regions of the viral DNA polymerase. Currently available second line agents for the treatment of herpesvirus infections--the pyrophosphate analogue foscarnet and the acyclic nucleoside phosphonate derivative cidofovir--also inhibit the viral DNA polymerase but are not dependent on prior viral-specific activation. Hence, viral DNA polymerase mutations may lead to a variety of drug resistance patterns which are not totally predictable at the moment due to insufficient information on specific drug binding sites on the polymerase. Although some CMV and HSV DNA polymerase mutants have been found to replicate less efficiently in cell cultures, further research is needed to correlate viral fitness and clinical outcome.
Research Center in Infectious Diseases, Centre Hospitalier Universitaire de Québec and Laval University, Québec City, Canada.
Christian
C
Gilbert
Julie
J
Bestman-Smith
Guy
G
Boivin
D000818:Animals; D000998:Antiviral Agents / Q000494:pharmacology / Q000627:therapeutic use*; D024921:Drug Resistance, Multiple, Viral / Q000235:genetics*; D006564:Herpesviridae / Q000187:drug effects* / Q000235:genetics; D006566:Herpesviridae Infections / Q000188:drug therapy* / Q000235:genetics; D006801:Humans; D009154:Mutation / Q000187:drug effects / Q000502:physiology
D000998:Antiviral Agents