Cytomegalovirus UL97 kinase mutations that confer maribavir resistance

The cytomegalovirus (CMV) UL97 kinase inhibitor maribavir (MBV) is undergoing clinical antiviral trials. Two clinical CMV isolates serially passaged in cell culture under MBV showed >20-fold increases in MBV resistance after the development of the UL97 mutation V353A in one of the isolates and of T409M in the other. Marker transfer studies confirmed that the V353A and T409M mutations conferred ∼15-fold and ∼80-fold increases, respectively, in MBV resistance without significantly affecting ganciclovir susceptibility. The 3 UL97 mutations now known to confer MBV resistance are located upstream of UL97 mutations linked to ganciclovir resistance, closer to kinase domains that are associated with adenosine triphosphate binding and phosphotransfer.