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Antimicrobial Agents and Chemotherapy, May 2003, p. 1707-1713, Vol. 47, No. 5
0066-4804/03/$08.00+0     DOI: 10.1128/AAC.47.5.1707-1713.2003
Copyright © 2003, American Society for Microbiology. All Rights Reserved.

Differential Mutation Patterns in Thymidine Kinase and DNA Polymerase Genes of Herpes Simplex Virus Type 1 Clones Passaged in the Presence of Acyclovir or Penciclovir

Tatsuo Suzutani,^1,2* Ken Ishioka,¹ Erik De Clercq,³ Kei Ishibashi,¹ Hisatoshi Kaneko,¹ Toshihiko Kira,¹ Koh-ichi Hashimoto,¹ Masahiro Ogasawara,² Katsuki Ohtani,² Nobutaka Wakamiya,² and Masayuki Saijo⁴

Department of Microbiology, Fukushima Medical University, Fukushima,¹ Department of Microbiology, Asahikawa Medical College, Asahikawa,² Department of Special Pathogen Laboratory, National Institute of Infectious Diseases, Tokyo, Japan,⁴ Rega Institute for Medical Research, B-3000 Leuven, Belgium³

Received 9 August 2002/ Returned for modification 17 October 2002/ Accepted 11 February 2003

A total of 21 clones of acyclovir (ACV)-resistant (ACV^r) herpes simplex virus type 1 (HSV-1) and 23 clones of penciclovir (PCV)-resistant (PCV^r) HSV-1, emerging during serial passages in the presence of ACV or PCV, were isolated under conditions excluding contamination of resistant mutants in the starting virus culture, and their mutations in the thymidine kinase (TK) and DNA polymerase (DNA Pol) genes were analyzed comparatively. Mutations in the TK genes from ACV^r mutants consisted of 50% single nucleotide substitutions and 50% frameshift mutations, while the corresponding figures for the PCV^r mutants were 4 and 96%, respectively (P < 0.001). Eight of the 21 ACV^r clones, but none of the 23 PCV^r clones, had mutations in DNA Pol. Only nucleotide substitution(s) could be detected in the DNA Pol gene, as the gene is essential for virus replication. Therefore, the results for the DNA Pol mutants are concordant with those for the TK mutants in that a single nucleotide substitution was commonly observed in the ACV^r, but not in the PCV^r, mutants. These results clearly point to differential mutation patterns between ACV^r and PCV^r HSV-1 clones.

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* Corresponding author. Mailing address: Department of Microbiology, Fukushima Medical University, Hikarigaoka 1, Fukushima 960-1295, Japan. Phone: 81-24-548-2111. Fax: 81-24-548-5072. E-mail: suzutani{at}fmu.ac.jp.

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Antimicrobial Agents and Chemotherapy, May 2003, p. 1707-1713, Vol. 47, No. 5
0066-4804/03/$08.00+0     DOI: 10.1128/AAC.47.5.1707-1713.2003
Copyright © 2003, American Society for Microbiology. All Rights Reserved.

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