The Genetic Basis of Human Cytomegalovirus Resistance and Current Trends in Antiviral Resistance Analysis

Abstract

Infections due to resistant human cytomegalovirus (CMV) are an emerging problem, particularly in immunocompromised hosts. When managing such patients, clinicians should be aware of the possibility of developing CMV antiviral resistance, especially while on prolonged therapy or if severe immunosuppression is present. CMV resistance to current antiviral agents is mediated by alterations in either the UL97 kinase or DNA polymerase, encoded by the UL97 and UL54 genes, respectively. UL97 mutations are capable of conferring resistance to ganciclovir, while UL54 mutations can impart resistance to ganciclovir, cidofovir, and foscarnet. If treatment failure is suspected to be due to antiviral resistance, CMV resistance analysis should be obtained. Phenotypic resistance assays performed on clinical isolates measure antiviral susceptibilities directly, but are laborious and time-consuming. Therefore, genotypic resistance analysis has become the more common means of diagnosing CMV resistance. Mutations in UL97 or UL54 may be clinically associated with resistance, but their effect on antiviral susceptibility must be confirmed by marker transfer techniques such as recombinant phenotyping.

Human cytomegalovirus antiviral drug resistance in hematopoietic stem cell transplantation: current state of the art

“…The rates of HCMV drug resistance vary widely, depending on type of patients, and several risk factors have already been identified: (1) patient and disease‐related factors such as SOT, underlying disease, type, and degree of host immunosuppression, and the occurrence of HCMV disease ; (2) treatment‐related factors such as prolonged antiviral therapy, suboptimal antiviral concentrations due to poor compliance or low drug absorption, and limited oral bioavailability ; and (3) viral factors such as the establishment of lifelong latency, which allows for late reactivations, the slow lytic replication cycle and higher viral load at the start of therapy . Indeed, drug resistance may be suspected if persistent or increasing blood viral load or overt HCMV disease occurs after at least 2 weeks of therapy .…”

Antiviral drug resistance in herpesviruses other than cytomegalovirus

“…In recent years, the resistance of CMV to antiviral drugs has been extensively reviewed elsewhere [6][7][8][9][10]. Among members of the Herpesviridae family, five of them (HSV-1, HSV-2, VZV and HHV-6A and B) are also the targets of antiviral strategies and will be the focus of this review.…”

Antiviral Drug Resistance in Herpesviruses

“…Therefore, only a small number of mutations clustered in a relatively short genomic region of the UL97 gene have been reported to confer resistance to GCV (Fig. 4a) (Gilbert et al 2002;Gilbert and Boivin 2005;Lurain and Chou 2010;James and Prichard 2011;Komatsu et al 2014). Ganciclovir-resistance mutations in the UL97 gene consist in single-nucleotide substitutions or in-frame deletions (Gilbert et al 2002;Gilbert and Boivin 2005).…”

“…4b) (Gilbert et al 2002;Gilbert and Boivin 2005;Lurain and Chou 2010;James and Prichard 2011;Komatsu et al 2014). The catalytic domain of the UL54 DNA polymerase consists of eight conserved domains (i.e., I to VII and d-region C) at its carboxyl-terminal portion.…”