Biochemical Characterization of a Virus Isolate, Recovered from a Patient with Herpes Keratitis, That Was Clinically Resistant to Acyclovir

Sarisky, Robert T.; Cano, Rachel; Nguyen, Tammy T.; Wittrock, Robert J.; Duffy, Karen E.; Clark, Phil; Bartus, Joan O.; Bacon, Teresa H.; Caspers-Velu, Laure; Hodinka, Richard L.; Leary, Jeffry J.
December 2001
Clinical Infectious Diseases;12/15/2001, Vol. 33 Issue 12, p2034
Academic Journal
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[sub50]) for this isolate was less than the accepted breakpoint for defining resistance to acyclovir (>2.0 µg/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[sub50] of acyclovir was more than 10 times the IC[sub50] for an acyclovir-susceptible control strain; (4) plaque-purified clonal isolates were resistant to acyclovir (IC[sub50]s, >2.0 µg/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.


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