Abstract
Many serious varicella-zoster virus (VZV) infections are treated with acyclovir (ACV). While there has not been clinical evidence of VZV resistance to ACV, its possibility warrants our understanding of its molecular basis. The majority of laboratory derived resistant VZV strains are deficient in thymidine kinase (TK) which.phosphorylates ACV. We studied the TK locus of 3 wild-type (TK+) and 3 ACV-resistant (TK-) strains. The 2.6 Kb Pst I-P VZV DMA fragment encoding TK was cloned from each strain and sequenced by the dideoxy chain termination method. The TK open reading frame is highly conserved with > 99% nucleotide homology among all strains. All TK+ strains are identical in predicted amino acid sequence in and around the putative enzyme binding sites for ATP and thymidine. However, one TK- mutant has a single base change near the thymidine binding site. The two other mutants contain premature stop codons which presumably result in a truncated, nonfunctional polypeptide. We propose that one mechanism of ACV resistance in VZV involves single base substitutions that lead to alterations in the substrate binding sites or overall secondary structure of the viral TK.
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