Phenotypic and genotypic analyses were done on 30 acyclovir-resistant and 5 acyclovir-susceptible herpes simplex virus (HSV) isolates (22 HSV type 1 and 13 HSV type 2) recovered from 24 subjects. All isolates were susceptible to foscaruet. The phenotypes of the acyclovir-resistant HSV isolates were as follows: 17 were thymidine kinase (TK) deficient, 12 had decreased TK activity (produced low amounts of viral TK) or TK with altered substrate specificity, and 1 was undetermined. Sequencing analysis of the HSV TK gene revealed that 14 (46.7%) of 30 acyclovir-resistant isolates had an insertion or deletion of 1 or 2 nucleotides, especially in homopolymer runs of Gs, Cs, and rarely in As. On the other hand, 16 (53.3%) of 30 acyclovir- resistant isolates had point mutations in conserved or nonconserved regions of the TK gene. In conclusion, HSV can develop multiple strategies to exhibit acyclovir resistance, including, in about half of the cases, frameshift mutations in homopolymer nucleotide stretches of the TK gene.
Bibliographical noteFunding Information:
Received: 22 December 1997; revised 18 February 1998. Presented in part: 36th Interscience Conference on Antimicrobial Agents and Chemotherapy, New Orleans, September 1996 (abstract H119). Financial support: Bayer Glaxo Wellcome, and the Canadian Society of Infectious Diseases (Young Investigator Research Award to G.B.); G.B. is a Scholar of the Medical Research Council of Canada. Reprints or correspondence: Dr. Guy Boivin, Centre Hospitalier de l’Univer-sité Laval, Rm. RC-709, 2705 Blvd. Laurier, Ste-Foy, Québec, Canada, G1V 4G2. *Present affiliation: Triangle Pharmaceuticals, Durham, North Carolina.