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Journal of Virology, February 2001, p. 1761-1769, Vol. 75, No. 4
0022-538X/01/$04.00+0   DOI: 10.1128/JVI.75.4.1761-1769.2001
Copyright © 2001, American Society for Microbiology. All rights reserved.

Characterization of Herpes Simplex Viruses Selected in Culture for Resistance to Penciclovir or Acyclovir

Robert T. Sarisky,1,* Matthew R. Quail,1 Philip E. Clark,1 Tammy T. Nguyen,1 Wendy S. Halsey,2 Robert J. Wittrock,1 Joan O'Leary Bartus,1 Marion M. Van Horn,2 Ganesh M. Sathe,2 Stephanie Van Horn,2 Michael D. Kelly,3 Teresa H. Bacon,4 and Jeffry J. Leary1

Molecular Virology and Host Defense,1 Genetic Technologies,2 and BioInformatics,3 SmithKline Beecham Pharmaceuticals, Collegeville, Pennsylvania, and SmithKline Beecham Consumer Healthcare, Weybridge, United Kingdom4

Received 30 August 2000/Accepted 16 November 2000

Penciclovir (PCV), an antiherpesvirus agent in the same class as acyclovir (ACV), is phosphorylated in herpes simplex virus (HSV)-infected cells by the viral thymidine kinase (TK). Resistance to ACV has been mapped to mutations within either the TK or the DNA polymerase gene. An identical activation pathway, the similarity in mode of action, and the invariant cross-resistance of TK-negative mutants argue that the mechanisms of resistance to PCV and ACV are likely to be analogous. A total of 48 HSV type 1 (HSV-1) and HSV-2 isolates were selected after passage in the presence of increasing concentrations of PCV or ACV in MRC-5 cells. Phenotypic analysis suggested these isolates were deficient in TK activity. Moreover, sequencing of the TK genes from ACV-selected mutants identified two homopolymeric G-C nucleotide stretches as putative hot spots, thereby confirming previous reports examining Acvr clinical isolates. Surprisingly, mutations identified in PCV-selected mutants were generally not in these regions but distributed throughout the TK gene and at similar frequencies of occurrence within A-T or G-C nucleotides, regardless of virus type. Furthermore, HSV-1 isolates selected in the presence of ACV commonly included frameshift mutations, while PCV-selected HSV-1 mutants contained mostly nonconservative amino acid changes. Data from this panel of laboratory isolates show that Pcvr mutants share cross-resistance and only limited sequence similarity with HSV mutants identified following ACV selection. Subtle differences between PCV and ACV in the interaction with viral TK or polymerase may account for the different spectra of genotypes observed for the two sets of mutants.

* Corresponding author. Mailing address: Department of Molecular Virology and Host Defense, SmithKline Beecham Pharmaceuticals, 1250 South Collegeville Rd., UP1450, Collegeville, PA 19426-0989. Phone: (610) 917-6724. Fax: (610) 917-4170. E-mail: robert_t_sarisky{at}sbphrd.com.

Journal of Virology, February 2001, p. 1761-1769, Vol. 75, No. 4
0022-538X/01/$04.00+0   DOI: 10.1128/JVI.75.4.1761-1769.2001
Copyright © 2001, American Society for Microbiology. All rights reserved.


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Copyright © 2001 by the American Society for Microbiology. All rights reserved.