Antiviral Drug Resistance of Human Cytomegalovirus

Abstract

SUMMARY The study of human cytomegalovirus (HCMV) antiviral drug resistance has enhanced knowledge of the virological targets and the mechanisms of antiviral activity. The currently approved drugs, ganciclovir (GCV), foscarnet (FOS), and cidofovir (CDV), target the viral DNA polymerase. GCV anabolism also requires phosphorylation by the virus-encoded UL97 kinase. GCV resistance mutations have been identified in both genes, while FOS and CDV mutations occur only in the DNA polymerase gene. Confirmation of resistance mutations requires phenotypic analysis; however, phenotypic assays are too time-consuming for diagnostic purposes. Genotypic assays based on sequencing provide more rapid results but are dependent on prior validation by phenotypic methods. Reports from many laboratories have produced an evolving list of confirmed resistance mutations, although differences in interpretation have led to some confusion. Recombinant phenotyping methods performed in a few research laboratories have resolved some of the conflicting results. Treatment options for drug-resistant HCMV infections are complex and have not been subjected to controlled clinical trials, although consensus guidelines have been proposed. This review summarizes the virological and clinical data pertaining to HCMV antiviral drug resistance.

Treatment of CMV infection after allogeneic hematopoietic stem cell transplantation

“…Different isoforms of kinase pUL97 greatly affect susceptibility of CMV to MBV efficacy [69]. There is generally no overlap between the kinase ATP binding site mutations and the UL97 mutations, that respectively confer MBV and GCV resistance, with the exception of a single p-loop mutation (F342S) involved in dual resistance to both drugs, even though it has not yet been observed in vivo [70,71].…”

Limits and patterns of cytomegalovirus genomic diversity in humans

“…HCMV is the leading cause of birth defects related to an infectious agent (1,2) and a primary cause of solid organ transplant failure (3). Prevention and clinical interventions for HCMV disease are limited by the absence of an effective vaccine, as well as resistance to antiviral drugs (4) and therapeutic neutralizing antibodies (5).…”

Cytomegalovirus (CMV) Encephalitis in HIV Patients

“…Viral UL97 kinase gene mutations confer ganciclovir resistance, but viral UL54 DNA polymerase gene mutations can confer resistance to any of the standard anti-CMV antiviral agents (ganciclovir, foscarnet, and cidofovir) [34,35]. Resistance is unusual in the first six weeks of therapy, but should be suspected when persistent or increasing CMV viral loads are reported or progression of disease occurs after several weeks of appropriate anti-CMV therapy [33,[36][37][38]. Treatment options are limited in this patient population, usually resulting in combination therapy with multiple antiviral agents -most commonly ganciclovir plus foscarnet [36].…”

“…Resistanceassociated mutations have been identified in the UL97 kinase gene and the UL54 DNA polymerase gene [31][32][33][34][35][36]. Resistance is characterized by an increase in drug concentration required to reduce the viral growth by 50% [33,34]. Viral UL97 kinase gene mutations confer ganciclovir resistance, but viral UL54 DNA polymerase gene mutations can confer resistance to any of the standard anti-CMV antiviral agents (ganciclovir, foscarnet, and cidofovir) [34,35].…”

“…The decline in reported resistance has been attributed to better control of CMV replication with ART. Resistanceassociated mutations have been identified in the UL97 kinase gene and the UL54 DNA polymerase gene [31][32][33][34][35][36]. Resistance is characterized by an increase in drug concentration required to reduce the viral growth by 50% [33,34].…”