A deletion mutation in region V of the cytomegalovirus DNA polymerase sequence confers multidrug resistance.

A patient with AIDS and cytomegalovirus (CMV) retinitis received ganciclovir and foscarnet for 20 and 5 months, respectively, with evidence of periodic disease progression. After this therapy, a CMV isolate from the patient was resistant to ganciclovir, foscarnet, and cidofovir. Sequence analysis showed a known ganciclovir resistance mutation in the viral UL97 phosphotransferase (L595F) and a new mutation in conserved region V of the DNA polymerase gene (pol) sequence (codons 981-982 deleted). The pol mutation was transferred to a laboratory CMV strain (Towne) by homologous recombination and selection with either ganciclovir or foscarnet. Recombinant viruses containing this deletion showed a 6-8-fold increased ganciclovir resistance and a 3-5-fold increased resistance to both foscarnet and cidofovir, compared with the wild-type CMV. A single mutation in region V of CMV pol can, therefore, confer multiple drug resistance in a clinical isolate.