Foscarnet resistance mutations mapping to atypical domains of the cytomegalovirus DNA polymerase gene

- CMV DNA polymerase amino acid changes S290R and E951D, among others, emerged in vitro to decrease foscarnet susceptibility.
- The amino terminal 1 structure domain of the CMV DNA polymerase is newly implicated in foscarnet resistance.
- Genotypic testing for foscarnet resistance should consider an increased range of UL54 codons.
- Drug susceptibility phenotyping in a modified retinal epithelial cell line gave similar results as in fibroblasts.

Human cytomegalovirus UL54 DNA polymerase gene mutations that confer foscarnet resistance in clinical practice typically cluster in the amino terminal 2, palm and finger domains. Exposure to foscarnet in cell culture selected for mutations elsewhere in UL54, including amino acid substitutions S290R in the amino terminal 1 domain and E951D in the palm 2 domain. These are newly confirmed to confer foscarnet resistance and slightly decreased ganciclovir susceptibility. Other emergent substitutions N495K, T552N and T838A are known to confer foscarnet resistance, while additional ones Q783R and V798A only slightly affected susceptibility. An expanded set of domains is involved in foscarnet resistance and its genotypic diagnosis.