title: Sequence Analysis of Herpes Simplex Virus 1 Thymidine Kinase and DNA Polymerase Genes from over 300 Clinical Isolates from 1973 to 2014 Finds Novel Mutations That May Be Relevant for Development of Antiviral Resistance.
abstract: A total of 302 clinical herpes simplex virus 1 (HSV-1) strains, collected over 4 decades from 1973 to 2014, were characterized retrospectively for drug resistance. All HSV-1 isolates were analyzed genotypically for nonsynonymous mutations in the thymidine kinase (TK) and DNA polymerase (Pol) genes. The resistance phenotype against acyclovir (ACV) and/or foscarnet (FOS) was examined in the case of novel, unclear, or resistance-related mutations. Twenty-six novel natural polymorphisms could be detected in the TK gene and 69 in the DNA Pol gene. Furthermore, three novel resistance-associated mutations (two in the TK gene and one in the DNA Pol gene) were analyzed, and eight known but hitherto unclear amino acid substitutions (two encoded in TK and six in the DNA Pol gene) could be clarified. Between 1973 and 2014, the distribution of amino acid changes related to the natural gene polymorphisms of TK and DNA Pol remained largely stable. Resistance to ACV was confirmed phenotypically for 16 isolates, and resistance to ACV plus FOS was confirmed for 1 isolate. Acyclovir-resistant strains were observed from the year 1995 onwards, predominantly in immunosuppressed patients, especially those with stem cell transplantation, and the number of ACV-resistant strains increased during the last 2 decades. The data confirm the strong genetic variability among HIV-1 isolates, which is more pronounced in the DNA Pol gene than in the TK gene, and will facilitate considerably the rapid genotypic diagnosis of HSV-1 resistance.
authors.affiliation: Institute of Virology and Antiviral Therapy, German Consulting Laboratory for HSV and VZV, Jena University Hospital, Friedrich-Schiller University, Jena, Germany.
authors.forename: Susanne
authors.initials: S
authors.lastname: Schmidt
authors.affiliation: Institute of Virology and Antiviral Therapy, German Consulting Laboratory for HSV and VZV, Jena University Hospital, Friedrich-Schiller University, Jena, Germany.
authors.forename: Kathrin
authors.initials: K
authors.lastname: Bohn-Wippert
authors.affiliation: Institute of Medical Statistics, Computer Sciences and Documentation, Jena University Hospital, Friedrich-Schiller University, Jena, Germany.
authors.forename: Peter
authors.initials: P
authors.lastname: Schlattmann
authors.affiliation: Institute of Virology and Antiviral Therapy, German Consulting Laboratory for HSV and VZV, Jena University Hospital, Friedrich-Schiller University, Jena, Germany.
authors.forename: Roland
authors.initials: R
authors.lastname: Zell
authors.affiliation: Institute of Virology and Antiviral Therapy, German Consulting Laboratory for HSV and VZV, Jena University Hospital, Friedrich-Schiller University, Jena, Germany Andreas.Sauerbrei@med.uni-jena.de.
authors.forename: Andreas
authors.initials: A
authors.lastname: Sauerbrei
mesh_terms: D000212:Acyclovir / Q000627:therapeutic use; D000293:Adolescent; D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D000998:Antiviral Agents / Q000627:therapeutic use; D002648:Child; D002675:Child, Preschool; D004259:DNA-Directed DNA Polymerase / Q000235:genetics*; D024882:Drug Resistance, Viral / Q000235:genetics*; D005260:Female; D017245:Foscarnet / Q000627:therapeutic use; D005838:Genotype; D006561:Herpes Simplex / Q000188:drug therapy / Q000821:virology; D018259:Herpesvirus 1, Human / Q000187:drug effects / Q000235:genetics*; D006801:Humans; D007223:Infant; D007231:Infant, Newborn; D008297:Male; D008875:Middle Aged; D009154:Mutation / Q000235:genetics; D011110:Polymorphism, Genetic / Q000235:genetics; D012189:Retrospective Studies; D017422:Sequence Analysis, DNA / Q000379:methods; D013937:Thymidine Kinase / Q000235:genetics*; D014764:Viral Proteins / Q000235:genetics; D055815:Young Adult
chemical_list: D000998:Antiviral Agents; D014764:Viral Proteins; D017245:Foscarnet; D013937:Thymidine Kinase; D004259:DNA-Directed DNA Polymerase; D000212:Acyclovir