Foscarnet is currently licensed for the treatment of human cytomegalovirus (HCMV) infection. Mutations proven to confer resistance to foscarnet have mostly been mapped to regions II, III and VI of the HCMV UL54-encoded DNA polymerase. We previously showed that sequential foscarnet-resistant HCMV isolates recovered from a patient with lymphoma had change N495K in region delta-C of the DNA polymerase. To evaluate the impact of change N495K on HCMV sensitivity to foscarnet, a recombinant HCMV strain carrying the mutation was produced by homologous recombination. The recombinant virus showed a 3.4-fold increase in foscarnet resistance, and remained sensitive to ganciclovir and cidofovir. In addition, the recombinant strain showed a reduction of infectious virus yield compared with its parent strain. Change N495K should be added to the list of mutations conferring resistance to foscarnet and be taken into account in the genotypic diagnosis of antiviral resistance.
References
1.
WeinbergA., JabsD.A., ChouS.for the cytomegalovirus retinitis and viral resistance study group and the adult AIDS clinical trials group cytomegalovirus laboratories. Mutations conferring foscarnet resistance in a cohort of patients with acquired immunodeficiency syndrome and cytomegalovirus retinitis.J Infect Dis2003; 187: 777–784.
2.
BaldantiF., UnderwoodM.R., StanatS.Single amino acid changes in the DNA polymerase confer foscarnet resistance and slow growth phenotype, while mutations in the UL97-encoded phosphotransferase confer ganciclovir resistance in three double-resistant human cytomegalovirus strains recovered from patients with AIDS.J Virol1996; 70: 1390–1395.
3.
CihlarT., FullerM.D., CherringtonJ.M.Characterization of drug resistance-associated mutations in the human cytomegalovirus DNA polymerase gene by using recombinant mutant viruses generated from overlapping DNA fragments.J Virol1998; 72: 5927–5936.
4.
ChouS., LurainN.S., ThompsonK.D., MinerR.C., DrewW.L.Viral DNA polymerase mutations associated with drug resistance in human cytomegalovirus.J Infect Dis2003; 188: 32–34.
5.
EriceA.Resistance of human cytomegalovirus to antiviral drugs.Clin Microbiol Rev1999; 12: 286–297.
6.
GilbertC., Bestman-SmithJ., BoivinG.Resistance of herpesviruses to antiviral drugs: clinical impacts and molecular mechanisms.Drug Resist Updat2002; 5: 88–114.
7.
Mousavi-JaziM., SchlossL., DrewW.L.Variations in the cytomegalovirus DNA polymerase and phosphotrans-ferase genes in relation to foscarnet and ganciclovir sensitivity.J Clin Virol2001; 23: 1–15.
8.
SpringerK.L., ChouS., LiS.How evolution of mutations conferring drug resistance affects viral dynamics and clinical outcomes of cytomegalovirus-infected hematopoietic cell transplant recipients.J Clin Microbiol2005; 43: 208–213.
9.
DucancelleA., BellocS., AlainS.Comparison of sequential cytomegalovirus isolates in a patient with lymphoma failing antiviral therapy.J Clin Virol2004; 29: 241–247.
10.
DucancelleA., GravisseJ., AlainS.Phenotypic characterization of cytomegalovirus DNA polymerase: a tool to study cytomegalovirus isolates resistant to foscarnet.J Virol Methods2005; 125: 145–151.
11.
ChouS., MarousekG., GuentzelS.Evolution of mutations conferring multidrug resistance during prophylaxis and therapy for cytomegalovirus disease.J Infect Dis1997; 176: 786–789.
12.
Mousavi-JaziM., SchlossL., WahrenB., BryttingM.Point mutations induced by foscarnet (PFA) in the human cytomegalovirus DNA polymerase.J Clin Virol2003; 26: 301–306.
13.
KuhnF.J., KnopfC.W.Herpes simplex virus type 1 DNA polymerase: mutational analysis of the 3′-5′-exonuclease domain.J Biol Chem1996; 271: 29245–29254.
14.
VisseB., HurauxJ., FilletA.M.Point mutations in the varicella-zoster virus DNA polymerase gene confer resistance to foscarnet and slow growth phenotype.J Med Virol1999; 59: 84–90.
