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Progressive Esophagitis from Acyclovir-Resistant Herpes Simplex: Clinical Roles for DNA Polymerase Mutants and Viral Heterogeneity?

Stephen L. Sacks, MD; Robert James Wanklin, BS; Donna E. Reece, MD; Karen A. Hicks, BA; Kenneth L. Tyler, MD; and Donald M. Coen, PhD
[+] Article, Author, and Disclosure Information

Grant Support: Supported in part by grants from the British Columbia Health Care Research Foundation and the National Institutes of Health (R01 AI 27209, P01-AI 24010, and R01-AI19838).

Requests for Reprints: Dr. Stephen L. Sacks, Division of Infectious Diseases, University Hospital—UBC Site, 2211 Wesbrook Mall, S-151, Vancouver, BC, Canada V6T 1W5.

Current Author Addresses: Dr. Sacks: Division of Infectious Diseases, The University of British Columbia, 2211 Wesbrook Mall, Vancouver, BC, Canada V6T 1W5.

Mr. Wanklin: Department of Pharmacology and Therapeutics, The University of British Columbia, 2176 Health Sciences Mall, Vancouver, BC, Canada V6T 1W5.

Dr. Reece: The Leukemia/Bone Marrow Transplantation Program of British Columbia, 910 West 10th Avenue, Vancouver, BC, Canada V5Z 4E3.

Dr. Tyler: Department of Microbiology and Molecular Genetics, Harvard Medical School, 200 Longwood Avenue, Boston, MA 02115.

Ms. Hicks and Dr. Coen: Department of Biological Chemistry and Molecular Pharmacology, Harvard Medical School, 250 Longwood Avenue, Boston, MA 02115.

©1989 American College of PhysiciansAmerican College of Physicians

Ann Intern Med. 1989;111(11):893-899. doi:10.7326/0003-4819-111-11-893
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Clinically acquired acyclovir resistance in herpes simplex has usually been associated with a deficiency in viral thymidine kinase, which, in turn, has been linked with attenuated virulence in animal models. Diminished pathogenicity in thymidine kinase-deficient isolates has been partly responsible for controversies about the clinical significance of antiviral resistance. We report on a series of resistant virus isolates from a patient who had severe, progressive esophagitis. These isolates had various thymidine kinase activities, ranging from 2.8% to 130% when compared with the activity of the isolate obtained before treatment; the resistant isolate 615 retained enzyme activity as well as neurovirulence in an encephalitis model. Plaque purification showed a heterogeneous mixture containing at least one acyclovir-resistant, foscarnet-resistant plaque isolate (615.8) fully able to phosphorylate acyclovir. The 3.3-kbp BamHI fragment containing most of the DNA polymerase gene from isolate 615.8 was purified and used to successfully transfer both acyclovir and foscarnet resistance. Acquisition of in-vitro acyclovir resistance was associated with progression of clinical disease, as well as with maintenance of pathogenicity in an animal model and at least one mutation in viral DNA polymerase. Patients with herpes simplex infections that progress during acyclovir therapy should be observed for acquisition of resistance in the setting of antiviral chemotherapy; future studies should also consider the presence of heterogeneous virus populations in such patients.





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