Patterns of resistance and sensitivity to antiviral compounds of drug-resistant strains of human cytomegalovirus selected in vitro

Drug-resistant human cytomegalovirus (HCMV) strains were selected in human embryonic lung (HEL) fibroblasts under pressure of the (S)-3-hydroxy-2-phosphonylmethoxypropyl (HPMP) derivatives of cytosine (HPMPC) and adenine (HPMPA), the 2-phosphonylmethoxyethyl (PME) derivative of 2,6-diaminopurine (PMEDAP), ganciclovir (GCV), acyclovir (ACV), and foscarnet (PFA). Drug susceptibility profiles of the different drug-resistant (i.e., GCVr, HPMPCr, HPMPAr, PFAr, ACVr, and PMEDAPr) strains were determined in HEL cells. A considerable degree of cross-resistance against GCV, HPMPC, and HPMPA occurred with the GCVr, HPMPCr, and HPMPAr strains. No changes in susceptibility to 9-(2-phosphonylmethoxyethyl)adenine (PMEA), PMEDAP, ACV, or PFA were detected for the HPMPCr, HPMPAr, and GCVr strains when compared to the wild-type virus. On the other hand, a significant degree of cross-resistance was noted with the PMEDAPr, PFAr, and ACVr strains against PMEA, PMEDAP, PFA, and ACV. No differences in susceptibility to HPMPC, HPMPA and GCV were observed for the ACVr, PFAr, and PMEDAPr strains relative to the wild type. The drug susceptibility profiles of the different resistant strains point to a common mechanism of HCMV resistance to PFA and the PME derivatives that is different from the mechanism of HCMV resistance to the HPMP derivatives.