Ganciclovir-resistant cytomegalovirus clinical isolates: mode of resistance to ganciclovir

Abstract

Cytomegalovirus strains with reduced in vitro susceptibilities to ganciclovir have been recovered from patients who failed long-term ganciclovir therapy. The ganciclovir-resistant clinical isolates in this study were unable to induce ganciclovir phosphorylation in virus-infected cells. The viral DNA polymerase function appeared unaltered in one genetically pure ganciclovir-resistant strain, compared with that of its wild-type ganciclovir-sensitive counterpart. All nine of the ganciclovir-resistant strains were susceptible to foscarnet. Moreover, these strains were sensitive to inhibition both by vidarabine and 1-(2'-deoxy-2'-fluoro-beta-D-arabinofuranosyl)-5-iodocytosine (FIAC), antiviral agents that are activated by cellular enzymes, and by (S)-1(3-hydroxy-2-phosphonylmethoxypropyl)cytosine (HPMPC), which is a monophosphate nucleoside analog. The in vitro resistance to ganciclovir of the ganciclovir-resistant clinical isolates studied was attributed to the inability of the cells infected with these isolates to phosphorylate ganciclovir; the virally encoded DNA polymerase did not appear to play a role in this ganciclovir resistance.

Mutations in human cytomegalovirus UL97 gene confer clinical resistance to ganciclovir and can be detected directly in patient plasma.

“…Sequential plasma samples were separated from the same heparinized blood specimens obtained for culture. 10 epidemiologically unrelated patients (patients [1][2][3][4][5][6][7][8][9][10] were selected on the basis of clinical resistance to ganciclovir therapy. The patients received an initial induction course of intravenous ganciclovir (5 mg/kg twice daily) followed by maintenance therapy of intravenous ganciclovir (5 mg/kg daily).…”

“…of in vitro resistant strains ( 1,2). Resistance in clinical isolates has been phenotypically associated with impaired ganciclovir phosphorylation in infected cells (3). However, the genotypic basis for clinical ganciclovir resistance has not been resolved.…”

3′‐Fluorine‐Substitution in 3‐Fluorocarbocyclic Oxetanocin A Augments the Drug's Inhibition of HHV‐6B Propagation in Chronically Infected Cultures

“…The 50% effective concentration (EC so) of C.OXT-G against HCMV has been shown to be comparable to that of GCV against HSV (21,36), despite its lower level of phosphorylation in the HCMV-infected cells (36). The finding that the triphosphate form of C.OXT-G is a potent competitive inhibitor of HCMV polymerase with a 2-log-more potent Ki than that of triphosphorylated GCV (33,36), suggested that the antiviral potency of C.OXTs is based on their ability to inhibit viral DNA polymerases.…”

Anti-HCMV Activity of Cidofovir in Combination with Antiviral Compounds and Immunosuppressive Agents: In-Vitro Analyses

“…Furthermore, cidofovir is effective against the majority of GCV resistant clinical isolates (those resulting from a defect in the protein coded for by UL97) (Stanat et et., 1991), as well as PFA resistant viruses generated in vitro (Snoeck et el., 1995) and in vivo (unpublished observations) as a result of PFA treatment alone. Since HCMV disease primarily occurs in two populations of patients (AIDS and organ transplant) who often receive multiple drugs for the treatment of more than one disease, it is critical to investigate the possible synergistic/antagonistic interactions that may occur between drug combinations.…”