Acyclovir susceptibility and genetic characteristics of sequential herpes simplex virus type 1 corneal isolates from patients with recurrent herpetic keratitis.
OBJECTIVE
The incidence and clinical significance of herpes simplex virus type 1 (HSV-1) acyclovir resistance were determined in patients with recurrent herpetic keratitis (RHK).


METHODS
Sequential corneal isolates (n = 39) from 15 immunocompetent patients with RHK were assayed for acyclovir susceptibility and genotyped by analyzing the hypervariable regions of the HSV-1 genes US1 and US12. The thymidine kinase (TK) gene of each isolate was sequenced, and the proportion of acyclovir-resistant viruses within isolates was determined.


RESULTS
Uniform acyclovir-resistant or acyclovir-sensitive sequential isolates were identified in 4 and 2 patients, respectively. Notably, the acyclovir susceptibility of sequential isolates changed from acyclovir sensitive to acyclovir resistant (5 patients) or from acyclovir resistant to acyclovir sensitive (3 patients). The acyclovir-resistant phenotype of the isolates correlated with the patient's unresponsiveness to acyclovir therapy. Combined analyses of the TK gene and genotype of sequential isolates showed that acyclovir-sensitive isolates contained multiple acyclovir-resistant variants of the same virus and that an identical acyclovir-resistant HSV-1 strain reappeared in the patient's cornea during RHK episodes.


CONCLUSIONS
Corneal HSV-1 isolates are mixtures of acyclovir-sensitive and acyclovir-resistant viruses that share the same genotype but have different TK sequences. Recovery of the same acyclovir-resistant virus during consecutive herpetic keratitis episodes suggests that acyclovir-resistant HSV-1 establishes latency and reactivates intermittently to cause acyclovir-refractory RHK.
Department of Virology, Erasmus Medical Centre, Rotterdam, the Netherlands.
Rui
R
Duan
Rory D
RD
de Vries
Jessica M
JM
van Dun
Freek B
FB
van Loenen
Albert D M E
AD
Osterhaus
Lies
L
Remeijer
Georges M G M
GM
Verjans
D000212:Acyclovir / Q000494:pharmacology*; D000328:Adult; D000368:Aged; D000998:Antiviral Agents / Q000494:pharmacology*; D024882:Drug Resistance, Viral / Q000235:genetics*; D018259:Herpesvirus 1, Human / Q000187:drug effects* / Q000235:genetics* / Q000302:isolation & purification; D006801:Humans; D016849:Keratitis, Herpetic / Q000188:drug therapy / Q000821:virology*; D008297:Male; D008875:Middle Aged; D011446:Prospective Studies; D017735:Virus Latency
D000998:Antiviral Agents; D000212:Acyclovir