Common and new acyclovir resistant herpes simplex virus-1 mutants causing bilateral recurrent herpetic keratitis in an immunocompetent patient.
We investigated thymidine kinase (tk) mutants isolated during multiple episodes of recurrent bilateral acyclovir resistant herpes simplex keratitis in an immunocompetent patient. From one eye, we found a single guanine insertion, previously shown to greatly reduce TK expression, and from the other, a previously unidentified substitution, which genetic experiments confirmed confers drug resistance. The substitution, although distant from substrate binding sites, reduced thymidine phosphorylation 10-20-fold, and acyclovir phosphorylation >100-fold. This phenotype should permit reactivation from latency to cause recurrent disease. The results may have implications for the prevalence and prevention of acyclovir resistance in patients with herpes simplex keratitis.
Department of Biological Chemistry and Molecular Pharmacology, Harvard Medical School, Boston, Massachusetts.
Dongli
D
Pan
Stephen B
SB
Kaye
Mark
M
Hopkins
Ruaidhri
R
Kirwan
Ian J
IJ
Hart
Donald M
DM
Coen
D000212:Acyclovir / Q000494:pharmacology*; D000328:Adult; D019943:Amino Acid Substitution; D000998:Antiviral Agents / Q000494:pharmacology*; D004279:DNA, Viral / Q000737:chemistry / Q000235:genetics; D024882:Drug Resistance, Viral; D018259:Herpesvirus 1, Human / Q000187:drug effects* / Q000302:isolation & purification; D006801:Humans; D016849:Keratitis, Herpetic / Q000821:virology*; D008297:Male; D008969:Molecular Sequence Data; D050505:Mutant Proteins / Q000235:genetics / Q000378:metabolism; D020125:Mutation, Missense; D010766:Phosphorylation; D017354:Point Mutation; D012008:Recurrence; D017422:Sequence Analysis, DNA; D013936:Thymidine / Q000378:metabolism; D013937:Thymidine Kinase / Q000235:genetics / Q000378:metabolism; D014764:Viral Proteins / Q000235:genetics / Q000378:metabolism
D000998:Antiviral Agents; D004279:DNA, Viral; D050505:Mutant Proteins; D014764:Viral Proteins; D013937:Thymidine Kinase; D013936:Thymidine; D000212:Acyclovir
acyclovir; antiviral drug resistance; herpes simplex keratitits; herpes simplex virus; thymidine kinase