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Antimicrobial Agents and Chemotherapy, October 1999, p. 2412-2416, Vol. 43, No. 10
0066-4804/99/$04.00+0
Copyright © 1999, American Society for Microbiology. All rights reserved.

Phenotypic and Genetic Characterization of Thymidine Kinase from Clinical Strains of Varicella-Zoster Virus Resistant to Acyclovir

Florence Morfin,1,* Danielle Thouvenot,1 Mireille De Turenne-Tessier,2 Bruno Lina,1 Michèle Aymard,1 and Tadamasa Ooka2

Laboratoire de Virologie des Hospices Civils de Lyon, 69373 Lyon,1 and Virologie Moléculaire UMR 5537 CNRS, Faculté de médecine RTH Laënnec, 69372 Lyon,2 France

Received 8 March 1999/Returned for modification 17 May 1999/Accepted 6 August 1999

Varicella-zoster virus (VZV) is a common herpesvirus responsible for disseminated or chronic infections in immunocompromised patients. Effective drugs such as acyclovir (ACV), famciclovir (prodrug of penciclovir), and foscarnet are available to treat these infections. Here we report the phenotypic and genetic characterization of four ACV-resistant VZV strains isolated from AIDS patients and transplant recipients. Sensitivity to six antiviral drugs was determined by an enzyme-linked immunosorbent assay, viral thymidine kinase (TK) activity was measured by comparing [3H]thymidine and 1-beta -D-arabinofuranosyl-[3H]thymine as substrates, and the TK gene open reading frame was sequenced. Three strains were found to be TK deficient, and the fourth was a mixed population composed of TK-positive and TK-deficient viruses. Each strain presented a unique TK gene mutation that could account for ACV resistance. In one strain, the deletion of two nucleotides at codon 215 induced a premature stop signal at codon 217. In another strain, a single nucleotide addition at codon 167 resulted in a premature stop signal at codon 206. In both other strains, we identified amino acid substitutions already described in other ACV-resistant VZV strains: either Gluright-arrowGly at residue 48 or Argright-arrowGly at residue 143. According to our work and data previously reported on resistant VZV strains, there are three areas in the TK gene where 71% of the mutations described to date are located. These areas are putative candidates for a genotypic diagnosis of ACV resistance.

* Corresponding author. Mailing address: Laboratoire de Virologie des Hospices Civils de Lyon, 8 avenue Rockefeller, 69373 Lyon Cedex 08, France. Phone: 33 478777029. Fax: 33 478014887. E-mail: fmorfin{at}rockefeller.univ-lyon1.fr.

Antimicrobial Agents and Chemotherapy, October 1999, p. 2412-2416, Vol. 43, No. 10
0066-4804/99/$04.00+0
Copyright © 1999, American Society for Microbiology. All rights reserved.


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