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

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An Erratum to this article was published on 23 June 2012

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.

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Acknowledgments

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

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Authors and Affiliations

  1. Institute of Medical Virology, Hospital of the Johann Wolfgang Goethe University, 60596, Frankfurt am Main, Germany

    Karoline Bleymehl & Jindrich Cinatl

  2. Department of Virology, Bernhard-Nocht-Institute for Tropical Medicine, Bernhard-Nocht-Strasse 74, 20359, Hamburg, Germany

    Jonas Schmidt-Chanasit

  3. Department of Virology, Clinical Virology Laboratory, Bernhard-Nocht-Strasse 74, 20359, Hamburg, Germany

    Jonas Schmidt-Chanasit

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  1. Karoline Bleymehl
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  2. Jindrich Cinatl
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  3. Jonas Schmidt-Chanasit
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Correspondence to Jonas Schmidt-Chanasit.

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Bleymehl, K., Cinatl, J. & Schmidt-Chanasit, J. Phenotypic and genetic characterization of varicella-zoster virus mutants resistant to acyclovir, brivudine and/or foscarnet. Med Microbiol Immunol 200, 193–202 (2011). https://doi.org/10.1007/s00430-011-0191-4

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