Aciclovir selects for ganciclovir-cross-resistance of human cytomegalovirus in vitro that is only in part explained by known mutations in the UL97 protein.

Phenotypically, ganciclovir-resistant human cytomegalovirus strains could be selected by aciclovir as effectively as by ganciclovir in vitro. Three clinical human cytomegalovirus isolates with different sensitivities against ganciclovir, aciclovir, foscarnet, and cidofovir, but without any mutation in the viral UL97 protein known to confer ganciclovir resistance, were propagated each in duplicate in the presence of ganciclovir or aciclovir. After drug selection, all 12 strains were less susceptible to ganciclovir (increase of 50% focus reduction dose between 2.1- and 31.5-fold) but were still sensitive to foscarnet and cidofovir; 7/12 exhibited a ganciclovir-resistant phenotype with a 50% focus reduction dose >30 microM, and in 6 out of these typical mutations in the UL97 coding region could be found by genotyping. All four strains selected from one isolate carried the identical UL97 mutation at amino acid position 460 (methionine to valine). The decreased sensitivity to ganciclovir and aciclovir in the other strains could neither be attributed to known UL97 mutations nor to mutations in the viral polymerase (UL54), which have been reported to induce resistance.