Abstract

Current drugs licensed for the treatment of herpes simplex virus (HSV) and varicella-zoster virus (VZV) infections include acyclovir (ACV), penciclovir (PCV), brivudin (BVDU) and foscarnet (FOS). Drugs approved for the treatment of cytomegalovirus (CMV) infections include ganciclovir (GCV), foscarnet (FOS), cidofovir (CDV) and fomivirsen. Except for formivirsen, all these drugs target the viral DNA polymerase. The nucleoside analogues ACV , PCV, GCV and BVDU require activation by viral kinases, i.e. thymidine kinase (TK) (HSV and VZV ) and UL97 protein (CMV). Therefore, resistance to these nucleoside analogues may arise by mutations in the enzymes responsible for the activation of these drugs or in the viral DNA polymerase. Resistance at the level of the viral DNA polymerase is observed with PFA , a direct inhibitor of viral DNA polymerases, or with acyclic nucleoside phosphonates (ANPs) that are independent of viral kinases for activation. Although emergence of resistance in herpesviruses is not a problem in the immunocompetent population, it is a concern among the immunocompromised population. The following points will be discussed in the seminar: • The characterization of HSV , VZV and CMV mutants arising under selective pressure with different classes of ANPs, as well as with ACV , PCV, GCV and BVDU . • How specific mutations affect viral pathogenicity. • Translational research: examples of drug-resistant mutants isolated from immunocompromised patients. • Overview of the mechanisms of antiviral drug resistance among poxviruses, including the identification of residues in the viral DNA polymerase conferring differential resistance to antipoxvirus drugs.