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

Robert T. Sarisky, Rachel Cano, Tammy T. Nguyen, Robert J. Wittrock, Karen E. Duffy, Phil Clark, Joan O. Bartus, Teresa H. Bacon, Laure Caspers-Velu, Richard L. Hodinka and Jeffry J. Leary
Clinical Infectious Diseases
Vol. 33, No. 12 (Dec. 15, 2001), pp. 2034-2039
Published by: Oxford University Press
Stable URL: http://www.jstor.org/stable/4482946
Page Count: 6
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Biochemical Characterization of a Virus Isolate, Recovered from a Patient with Herpes Keratitis, That Was Clinically Resistant to Acyclovir
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Abstract

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 (IC₅₀) 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 IC₅₀ of acyclovir was more than 10 times the IC₅₀ for an acyclovir-susceptible control strain; (4) plaque-purified clonal isolates were resistant to acyclovir (IC₅₀s, >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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