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Medical Microbiology and Immunology

, Volume 200, Issue 3, pp 193–202 | Cite as

Phenotypic and genetic characterization of varicella-zoster virus mutants resistant to acyclovir, brivudine and/or foscarnet

  • Karoline Bleymehl
  • Jindrich Cinatl
  • Jonas Schmidt-ChanasitEmail author
Original Investigation

Abstract

The treatment of varicella-zoster virus (VZV) reactivation is based on nucleoside analogues acyclovir (ACV) and bromevinyldeoxyuridine (BVdU) and a phosphonic acid derivative (PFA). Drug-resistant mutants of 3 wild-type (WT) VZV strains were obtained by exposure of human retinal pigment epithelial (hRPE) cells inoculated with cell-free WT virus at increasing concentrations of ACV, BVdU, and PFA. In addition to single-drug resistance, a cross-resistance of isolates vs. ACV was observed for PFA-resistant strains. Single-nucleotide (nt) exchanges resulting in amino acid (aa) substitutions were observed within the DNA polymerase (ORF 28) and/or thymidine kinase (ORF 36) of 3 of 3 ACV-, 2 of 3 BVdU-, and 3 of 3 PFA-resistant strains. Interestingly, aa substitutions were also observed within the immediate-early regulatory protein and major transactivator IE 62 (ORF 62), and the envelope glycoprotein (g) I (ORF 67) of the BVdU-resistant mutant of strain PP. No aa substitutions were observed in the protein sequences of gene products encoded by ORF 5 (gK, a glycoprotein arranging exocytosis of viral-loaded vacuoles), ORF 14 (gC), ORF 31 (gB), ORF 37 (gH), ORF 47 (protein kinase, involved in major phosphorylating processes), ORF 60 (gL, important for syncytia forming of infected cells in combination with gH), ORF 63 (major transactivator, part of the tegument), and ORF 68 (gE, triggers fusion of viral loaded vacuoles with cell membranes by heterodimerizing with gI). Phenotypic analysis revealed a slow-growth phenotype and a formation of smaller plaques of resistant mutants. Future studies should prove the presence of those resistant mutants in herpes zoster patients and the potential consequences of their putative reduced fitness on the success of therapeutical interventions.

Keywords

VZV Acyclovir Bromevinyldeoxyuridine Phosphonoformiat Brivudine IE62 Glycoprotein Resistance 

Notes

Acknowledgments

The work was supported by the Hospital of the Johann Wolfgang Goethe University.

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Copyright information

© Springer-Verlag 2011

Authors and Affiliations

  • Karoline Bleymehl
    • 1
  • Jindrich Cinatl
    • 1
  • Jonas Schmidt-Chanasit
    • 2
    • 3
    Email author
  1. 1.Institute of Medical VirologyHospital of the Johann Wolfgang Goethe UniversityFrankfurt am MainGermany
  2. 2.Department of VirologyBernhard-Nocht-Institute for Tropical MedicineHamburgGermany
  3. 3.Department of VirologyClinical Virology LaboratoryHamburgGermany

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