Biochemical characterization of a virus isolate, recovered from a patient with herpes keratitis, that was clinically resistant to acyclovir.
In vitro susceptibility assays of herpes simplex virus (HSV) do not necessarily correlate with treatment outcome. An HSV type 1 (HSV-1) isolate, N4, recovered from a patient who presented with herpes keratitis with localized immunosuppression, was characterized for susceptibility. Although the 50% inhibitory concentration (IC(50)) for this isolate was less than the accepted breakpoint for defining resistance to acyclovir (>2.0 microg/mL), the following lines of evidence suggest that the isolate was acyclovir resistant: (1) the clinical history confirmed that the infection was nonresponsive to acyclovir; (2) the in vitro susceptibility was similar to that of a thymidine kinase (TK)-negative, acyclovir-resistant virus SLU360; (3) the IC(50) of acyclovir was more than 10 times the IC(50) for an acyclovir-susceptible control strain; (4) plaque-purified clonal isolates were resistant to acyclovir (IC(50)s, >2.0 microg/mL); and (5) biochemical studies indicated that the HSV-1 N4 TK was partially impaired for acyclovir phosphorylation. Although residue changes were found in both the viral tk and pol coding regions of HSV-1 N4, characterization of a recombinant virus expressing the HSV-1 N4 polymerase suggested that the TK and Pol together conferred the acyclovir-resistance phenotype.
Sarisky
R T
RT
Department of Host Defense, Antimicrobial and Host Defense Center of Excellence for Drug Discovery, GlaxoSmithKline Pharmaceuticals, Collegeville, PA, 19426-0989, USA. robert_t_sarisky@gsk.com
Cano
R
R
Nguyen
T T
TT
Wittrock
R J
RJ
Duffy
K E
KE
Clark
P
P
Bartus
J O
JO
Bacon
T H
TH
Caspers-Velu
L
L
Hodinka
R L
RL
Leary
J J
JJ
D000212:Acyclovir / Q000494:pharmacology*; D000368:Aged; D000998:Antiviral Agents / Q000494:pharmacology*; D004352:Drug Resistance, Microbial; D006561:Herpes Simplex / Q000821:virology*; D018259:Herpesvirus 1, Human / Q000187:drug effects* / Q000302:isolation & purification; D006801:Humans; D007634:Keratitis / Q000821:virology*; D008297:Male; D008826:Microbial Sensitivity Tests; D010641:Phenotype
D000998:Antiviral Agents; D000212:Acyclovir