Analysis of the thymidine kinase of a herpes simplex virus type 1 isolate that exhibits resistance to (E)-5-(2-bromovinyl)-2'-deoxyuridine.

Analysis of the thymidine kinase of a herpes simplex virus type 1 isolate that exhibits resistance to (E)-5-(2-bromovinyl)-2'-deoxyuridine.

Wilber B A; Docherty J J

The Journal of general virology

1994

1994-07

The mechanism responsible for the decreased sensitivity of a clinical herpes simplex virus type 1 (HSV-1) isolate, HSV-145, to (E)-5-(2-bromovinyl)-2'-deoxyuridine (BVDU) was examined. Measurements of 50% inhibitory doses of several drugs demonstrated that although HSV-145 was sensitive to phosphonoacetic acid, adenine arabinoside and acyclovir, its sensitivity to BVDU and 5-(2-chloroethyl)-2'-deoxyuridine was significantly less than that normally observed for HSV-1. Analysis of the thymidylate kinase (TMP-K) activity of HSV-145 thymidine kinase (TK) demonstrated a decreased level of TMP-K activity when compared to HSV-1 TK. The TMP-K activity of HSV-145 resembled that observed for HSV-2 and the TK-deficient strain HSV-1 TK-7. When the nucleotide sequence of the HSV-145 TK gene was compared to that of the HSV-1 strains C1(101) and SC16 a single nucleotide substitution (G changed to A at base position 502) was detected which would result in the substitution of threonine at amino acid position 168 for alanine. The substitution is the same as that for the laboratory-derived BVDU-resistant virus HSV-1 SC16B3. Collectively, these studies highlight the importance of amino acid conservation at position 168 of the HSV-1 TK in conferring efficient TMP-K activity and BVDU sensitivity.

Acyclovir/pharmacology; Amino Acid Sequence; Antiviral Agents/metabolism/*pharmacology; Base Sequence; Binding Sites; Bromodeoxyuridine/*analogs & derivatives/metabolism/pharmacology; Deoxyuridine/analogs & derivatives/pharmacology; DNA; Drug Resistance; Herpesvirus 1; Human/drug effects/*enzymology/genetics; Humans; Kinetics; Microbial; Molecular Sequence Data; Phosphonoacetic Acid/pharmacology; Phosphorylation; Point Mutation/genetics; Sequence Analysis; Thymidine Kinase/genetics/metabolism; Thymidine/metabolism; Vidarabine/pharmacology

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