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Journal of Virology, July 2006, p. 6568-6574, Vol. 80, No. 13
0022-538X/06/$08.00+0     doi:10.1128/JVI.00155-06
Copyright © 2006, American Society for Microbiology. All Rights Reserved.

Low-Level Expression and Reversion both Contribute to Reactivation of Herpes Simplex Virus Drug-Resistant Mutants with Mutations on Homopolymeric Sequences in Thymidine Kinase

Anthony Griffiths,{dagger} Malen A. Link,{ddagger} Caroline L. Furness,§ and Donald M. Coen*

Department of Biological Chemistry and Molecular Pharmacology, Harvard Medical School, Boston, Massachusetts 02115

Received 23 January 2006/ Accepted 9 April 2006

Many acyclovir-resistant herpes simplex virus isolates from patients contain insertions or deletions in homopolymeric sequences in the thymidine kinase (TK) gene (tk). Viruses that have one (G8) or two (G9) base insertions in a run of seven G's (G string) synthesize low levels of active TK (TK-low phenotype), evidently via ribosomal frameshifting. These levels of TK can suffice to permit reactivation from latently infected mouse ganglia, but in a majority of ganglia, especially with the G9 virus, reactivation of virus that has reverted to the TK-positive phenotype predominates. To help address the relative contributions of translational mechanisms and reversion in reactivation, we generated viruses with a base either inserted or deleted just downstream of the G string. Both of these viruses had a TK-low phenotype similar to that of the G8 and G9 viruses but with less reversion. Both of these viruses reactivated from latently infected trigeminal ganglia, albeit inefficiently, and most viruses that reactivated had a uniformly TK-low phenotype. We also generated viruses that have one insertion in a run of six C's or one deletion in a run of five C's. These viruses lack measurable TK activity. However, they reactivated from latently infected ganglia, albeit inefficiently, with the reactivating viruses having reverted to the wild-type TK phenotype. Therefore, for G-string mutants, levels of active TK as low as 0.25% generated by translational mechanisms can suffice for reactivation, but reversion can also contribute. For viruses that lack TK activity due to mutations on other homopolymeric sequences, reactivation can occur via reversion.

* Corresponding author. Mailing address: Department of Biological Chemistry and Molecular Pharmacology, Harvard Medical School, 250 Longwood Ave., Boston, MA 02115. Phone: (617) 432-1691. Fax: (617) 432-3833. E-mail: don_coen{at}hms.harvard.edu.

{dagger} Present address: Department of Virology and Immunology, Southwest Foundation for Biomedical Research, 7620 NW Loop 410, San Antonio, TX 78227.

{ddagger} Present address: Harvard Medical School at Beth Israel Deaconess Medical Center, Boston, MA 02215.

§ Present address: Department of Paediatrics, Royal Berkshire Hospital, London Road, Reading RG1 5AN, United Kingdom.

Journal of Virology, July 2006, p. 6568-6574, Vol. 80, No. 13
0022-538X/06/$08.00+0     doi:10.1128/JVI.00155-06
Copyright © 2006, American Society for Microbiology. All Rights Reserved.



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