The human cytomegalovirus DNA polymerase: structure, inhibitors and mechanisms of resistance

Abstract

The human cytomegalovirus (HCMV) DNA polymerase (pUL54), a member of DNA polymerase family B, is a DNA-dependant polymerase, which possesses both polymerase and 3'-5'exonuclease enzymatic functions. pUL54 is the specific target of the anti-HCMV drugs currently used for the treatment of severe HCMV infections, including ganciclovir and its prodrug (valganciclovir), cidofovir, foscarnet. pUL54 is related to the DNA polymerases of other herpes viruses through a series of eight conserved domains. The DNA polymerase alterations involved in resistance to antiviral drugs are mostly located in these conserved domains. Some of those affect the enzymatic functions (polymerase and/or exonuclease) of the protein and/or the fitness of the mutated viruses. Phenotypic and genotypic assays are used to study the susceptibility to antiviral drugs of HCMV strains. The phenotype of mutated polymerase is a new tool to characterize mutations suspected to confer resistance to foscarnet. Significant advances have been made in the understanding of the molecular mechanisms of HCMVdrug resistance. However, cristallographic data are needed to design new antiviral agents.