METABOLISM OF GANCICLOVIR AND CIDOFOVIR IN CELLS INFECTED WITH DRUG-RESISTANT AND WILD-TYPE STRAINS OF MURINE CYTOMEGALOVIRUS

Murine cytomegalovirus (MCMV) has been used extensively as an animal m odel for human cytomegalovirus (HCMV). Understanding drug resistance a nd its treatment in MCMV may lead to more effective treatments of HCMV disease. Most ganciclovir-resistant HCMV clinical isolates exhibit a decreased capacity to induce ganciclovir phosphorylation (to its biolo gically active form) in infected cells. Using an MCMV strain resistant to both ganciclovir and cidofovir, the intracellular metabolism of th ese drugs was studied to determine if MCMV resistance correlates with decreases in drug phosphorylation. The wild-type (WT) MCMV used for co mparison was inhibited in plaque reduction assays, by ganciclovir and cidofovir by 50% at 5.1 and 0.24 mu M, respectively; the resistant str ain was inhibited at 72 and 2.7 mu M, respectively. In uninfected, WT, or resistant virus-infected cells, the extent of metabolism of 10 mu M ganciclovir or 1 mu M cidofovir to intracellular triphosphorylated s pecies was similar. Phosphorylation and catabolism (following drug rem oval) rates over time were also similar. Intracellular levels of ganci clovir triphosphate and cidofovir diphosphate increased less than two- fold with increasing multiplicity of virus infection. Because few diff erences in drug phosphorylation between WT and resistant virus-infecte d cells were found, virus resistance to ganciclovir and cidofovir appa rently is not linked to altered drug phosphorylation. Since the viral DNA polymerase is the antiviral target for these compounds, the resist ant MCMV is most likely a DNA polymerase mutant. (C) 1997 Elsevier Sci ence B.V.