MECHANISMS OF HERPES-VIRUS RESISTANCE

The introduction of virus-specific anti-herpes virus agents such as acyclovir, ganciclovir and Foscarnet has had a significant impact on the management of herpes virus infections. The use of specifically acting antimicrobial agents, however, raises the question of drug resistance. Exposure in cell culture of herpes virus to these agents results in the selection of drug-resistant variants, with resistance being due to alterations in the genes encoding the target enzymes involved in the mechanism of action of the drugs concerned, e.g. in the case of acyclovir resistance occurs as a result of deletions or alterations in the thymidine kinase (TK) or alterations in DNA polymerase genes. Pathogenicity studies reveal that drug-resistant variants are disadvantaged, in particular the TK deletion variants which are less pathogenic and unable to reactivate from latent infections. Extensive studies in cell culture and animal models with herpes viruses have provided an understanding of the mechanisms of resistance and more recently these findings have been correlated with the clinical experience. The incidence of virus resistance in immunocompetent patients is extremely rare, whereas resistance has infrequently been reported in immunocompromised individuals where exposure to drug is prolonged. However, the understanding of the mechanisms and consequences of virus resistance gained in cell culture and in animal models has led to the successful management of resistant episodes in the clinic, either by temporary removal of the selection pressure or by providing alternative therapies.