A New Locus of Drug Resistance in the Human Cytomegalovirus UL56 Gene Revealed by in vitro Exposure to Letermovir and Ganciclovir [PublishAheadOfPrint]

Letermovir is a human cytomegalovirus (CMV) terminase inhibitor recently approved as prophylaxis in stem cell transplant recipients. In further studies of emerging drug resistance, a baseline laboratory CMV strain was serially propagated in cell culture under a combination of letermovir and ganciclovir. In 8 experiments, UL56 terminase gene mutations were detected beginning at 10 passages, including novel amino acid substitutions V236A, L328V and A365S, in a region previously associated with letermovir resistance. Outside this region, UL56 substitution C25F was detected at moderate drug concentrations in 2 experiments, as either the first detected mutation, or adding to a preexisting substitution V231L. In all cases, mutation at UL56 codon 325 conferring absolute letermovir resistance eventually developed at a median of 20 passages. No UL97 kinase or UL54 DNA polymerase mutations relevant to ganciclovir resistance were detected until many passages after the first detection of UL56 mutations. UL56 substitutions V236A, L328V and A365S were shown to confer borderline or low-grade letermovir resistance, while C25F conferred 5.4-fold increased letermovir resistance (EC50) by itself and 46-fold in combination with V231L. The evolution of resistance mutations sooner in UL56 than in UL54 or UL97 is consistent with prior in vitro observations, and UL56 codon 25 is a genetic locus for letermovir resistance distinct from those previously described.

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