Geno- and Phenotypic Characterization of Human Cytomegalovirus Mutants Selected In Vitro after Letermovir (AIC246) Exposure

Letermovir is a novel antiviral compound currently in clinical development for the prevention of human cytomegalovirus (HCMV) infections. In contrast to all currently approved anti-HCMV drugs that target the viral DNA polymerase, letermovir acts via a distinct mode of action involving the viral terminase subunit pUL56. To extend our understanding of potential leter-movir resistance mechanisms, we used marker transfer to characterize mutations identified in letermovir-resistant HCMV vari-ants that were selected in cell culture. Human cytomegalovirus (HCMV) disease continues to be aserious and life-threatening condition in immunocompro-mised patients such as transplant recipients. Currently approved anti-HCMV drugs, including (val)ganciclovir, cidofovir, and fos-carnet, are associated with profound toxicity as well as drug resis-tance that restricts their long-term clinical benefit. All these sub-stances ultimately target the viral DNA polymerase (pUL54), though ganciclovir requires prior activation by the viral pUL97 kinase. Accordingly, mutations in open reading frame (ORF) UL97 are associated with (val)ganciclovir resistance whereas mu-tations in ORF UL54 can confer cross-resistance to all approve