A point mutation in the thymidine kinase gene is responsible for acyclovir-resistance in herpes simplex virus type 2 sequential isolates.
A number of HSV-2 isolates, sequentially recovered from ulcerative ano-genital lesions of an AIDS patient during a prolonged treatment with acyclovir (ACV), have been studied at the molecular level. All of them were highly resistant to ACV (ACV-r) and shown to be virtually deficient in thymidine kinase (TK) activity. The ACV-r phenotype was demonstrated to be due to the production of truncated TK polypeptide. Structural alteration of this gene, as shown in one isolate, was caused by a chain-terminating mutation that originated from a cytidine deletion at position 520 of the TK open reading frame. This mutation generated a TGA stop codon 27 nucleotides downstream. An additional isolate was also recovered following ACV discontinuation and after a cycle of treatment with foscarnet. This isolate had lost the ACV-r trait and was characterized by a wild type TK sequence and by the production of a functional enzyme. Data presented confirm that a prolonged treatment with acyclovir can easily select ACV-r HSV-2 isolates carrying a TK- phenotype caused by a frameshift mutation. Although recovered from lesions tributary of different myelomers, these isolates may belong to the same strain that has undergone multiple cycles of reactivation and has possibly mutated during its axonal route to the skin.
Palù
G
G
Institute of Microbiology, University of Padova Medical School, Italy.
Gerna
G
G
Bevilacqua
F
F
Marcello
A
A
D000163:Acquired Immunodeficiency Syndrome / Q000150:complications; D000212:Acyclovir / Q000494:pharmacology*; D000328:Adult; D001483:Base Sequence; D004279:DNA, Viral / Q000235:genetics; D004352:Drug Resistance, Microbial / Q000235:genetics; D005814:Genes, Viral; D006558:Herpes Genitalis / Q000150:complications / Q000188:drug therapy / Q000382:microbiology; D006801:Humans; D008297:Male; D008969:Molecular Sequence Data; D009154:Mutation; D009894:Opportunistic Infections / Q000150:complications / Q000188:drug therapy / Q000382:microbiology; D018139:Simplexvirus / Q000201:enzymology / Q000235:genetics* / Q000302:isolation & purification; D013937:Thymidine Kinase / Q000235:genetics*
D004279:DNA, Viral; D013937:Thymidine Kinase; D000212:Acyclovir