Clinical relationship of genotype and antiviral drug resistance in cytomegalovirus infections

Cytomegalovirus (CMV) is a double-stranded enveloped DNA virus belonging to the Betaherpesvirinae subfamily of the Herpesviridae family. CMV infections manifest with a high risk of mortality and morbidity in individuals with suppressed immune systems. Ganciclovir is the primary choice for the prevention and treatment of CMV infections. Through phosphorylation mediated by the CMV UL97 serine-threonine protein kinase enzyme, ganciclovir is converted to ganciclovir-monophosphate. Ganciclovir- monophosphate becomes active by further conversion to ganciclovir-triphosphate through host cell protein kinases, serving as a substrate for CMV DNA polymerase. Incorporation of ganciclovir-triphosphate into the DNA chain leads to termination of CMV DNA synthesis. Our study aims to investigate the relationship between the genotypes of CMV isolated from samples of patients in various diagnostic groups and the presence of CMV antiviral drug resistance mutations in connection with patient clinical outcomes. In this study conducted between 2018 and 2023 at Aydın Adnan Menderes University Hospital, CMV genotyping was performed on 44 patient samples with a CMV DNA viral load of 103 copies/ml and above, and with a sufficient quantity. Additionally, CMV antiviral drug resistance mutations were investigated in 8 patient samples with a CMV DNA viral load of 104 copies/ml and above, and with a sufficient quantity. For CMV genotyping, a region of 474 bp in the UL55 gene and for CMV antiviral drug resistance investigation, a region of 835 bp in the UL97 gene were analyzed using the Sanger sequencing method (ABI 3500 Genetic Analyzer, USA). Our study identified that CMV infections were primarily caused by gB1 and gB3 genotypes, with a higher prevalence of gB3 genotype in bone marrow transplant recipients. CMV infections with the gB4 genotype were found to be the least frequent compared to other genotypes. The rate of mixed genotypes in our study was relatively lower than in other studies. Moreover, in cases where mixed genotypes were detected, the CMV DNA viral load was observed to be higher, consistent with findings from other studies. In patients with CMV pneumonia symptoms, the gB3 genotype was significantly more prevalent. Amino acid changes identified in the UL97 gene region in our study was not involved in the previously reported mutations known to cause resistance. It would be appropriate to investigate whether the amino acid changes we observed for the first time in the functional region of the pUL97 enzyme contribute to antiviral drug resistance through phenotypic methods. It is suggested that further research should be conducted through controlled prospective studies with a large number of samples, encompassing different geographic regions and diverse patient groups. This would help determine the distribution of CMV genotypes and antiviral drug resistance and explore their impact on the course of the disease.