Drug resistance patterns of herpes simplex virus isolates from patients treated with acyclovir.
A decrease in the in vitro sensitivity to acyclovir (ACV) was observed in successive isolates of herpes simplex virus type 1 from three immunocompromised patients during intravenous therapy with this drug. The ACV-resistant isolate from patient 1 was cross-resistant to dihydroxypropoxymethylguanine and bromovinyldeoxyuridine, but still susceptible to three fluoro-substituted pyrimidines, 2'-fluoro-5-iodo-1-beta-D-arabinofuranosylcytosine (FIAC), 2'-fluoro-5-iodo-1-beta-D-arabinofuranosyluracil (FIAU), and 2'-fluoro-5-iodo-1-beta-D-arabinofuranosylthymine (FMAU). The thymidine kinase (TK) from the resistant isolate showed a 50-fold or greater reduction in affinity for thymidine, FIAU, FMAU, and ACV, but the total enzyme activity was similar to that of the sensitive isolate. The ACV-resistant isolate from patient 2 was also resistant to dihydroxypropoxymethylguanine, bromovinyldeoxyuridine, and the fluoro-substituted compounds; TK activity for this isolate was less than 1% of the patient's pretherapy isolate. An isolate obtained during a subsequent recurrence in patient 2 was susceptible to ACV and the other TK-dependent agents. The ACV-resistant isolate from patient 3 was partially resistant to FIAC and FIAU but still susceptible to FMAU; the viral TK had a 10-fold-lower affinity for ACV, FIAU, and FMAU than did the sensitive pretherapy isolate, while the level of TK activity detected was reduced to 6%. In none of the isolates studied was a change in sensitivity to phosphonoformic acid observed. Compared with the corresponding pretherapy ACV-sensitive isolates, there was a 30-fold decrease in neurovirulence for mice of the two drug-resistant isolates with diminished levels of thymidine-phosphorylating activity and no change in virulence for the third isolate. These findings indicate that mixed patterns of drug-resistance to TK-dependent antiviral compounds can occur in clinical isolates, resulting from changes in either the amount or the affinity of viral TK activity.
D000212:Acyclovir / Q000031:analogs & derivatives / Q000494:pharmacology* / Q000627:therapeutic use; D000328:Adult; D000818:Animals; D000998:Antiviral Agents / Q000494:pharmacology*; D001086:Arabinofuranosyluracil / Q000031:analogs & derivatives / Q000494:pharmacology; D001973:Bromodeoxyuridine / Q000031:analogs & derivatives / Q000494:pharmacology; D003561:Cytarabine / Q000031:analogs & derivatives / Q000494:pharmacology; D004352:Drug Resistance, Microbial; D005260:Female; D015774:Ganciclovir; D006801:Humans; D008297:Male; D051379:Mice; D008807:Mice, Inbred BALB C; D018139:Simplexvirus / Q000187:drug effects* / Q000201:enzymology / Q000302:isolation & purification / Q000472:pathogenicity; D013283:Stomatitis, Herpetic / Q000188:drug therapy* / Q000382:microbiology; D013937:Thymidine Kinase / Q000378:metabolism; D014774:Virulence / Q000187:drug effects
D000998:Antiviral Agents; D003561:Cytarabine; C020235:brivudine; D001086:Arabinofuranosyluracil; C026023:fiacitabine; D013937:Thymidine Kinase; D001973:Bromodeoxyuridine; C034935:clevudine; D015774:Ganciclovir; D000212:Acyclovir