Mechanisms of Resistance to Antiviral Agents

Abstract

Understanding the mechanisms of viral drug resistance is critical to the clinical management of individuals receiving antiviral therapy, the development of new antiviral drugs, and the surveillance of drug resistance. This chapter reviews the mechanisms of resistance to antiviral agents used to treat seven common viral infections, i.e., infections with herpes simplex virus (HSV), cytomegalovirus (CMV), varicella-zoster virus (VZV), human immunodeficiency virus types 1 and 2 (HIV-1 and HIV-2), influenza A and B viruses, hepatitis B virus (HBV), and hepatitis C virus (HCV). Antiviral drug resistance is usually mediated by mutations in the molecular targets of drug therapy, and the development of drug resistance is the most compelling evidence that an antiviral drug acts by specifically inhibiting a virus rather than its cellular host. Drug-resistant viruses are identified by in vitro passage experiments with increasing concentrations of an inhibitory drug and by ex vivo analysis of virus isolates obtained from individuals receiving antiviral therapy. Antiviral agents, mechanisms of resistance, and mutations involved in drug resistance in herpesviruses are summarized in a tabular form. Most TK mutants are classified as TK negative, usually arising from frameshift or stop mutations that delete important functional domains, or TK partial, when a mutation reduces the phosphorylation of both natural nucleosides and antiviral drugs. Nucleoside analog RdRp inhibitors appear to be equally active against the different HCV genotypes. The genetic barrier to nucleoside analog resistance also appears to be higher than that for the other two main classes of HCV inhibitors.