title: Single nucleotide polymorphisms of thymidine kinase and DNA polymerase genes in clinical herpes simplex virus type 1 isolates associated with different resistance phenotypes.
abstract: The role of mutations in the thymidine kinase (TK, UL23) and DNA polymerase (pol, UL30) genes of herpes simplex virus (HSV) for development of different resistance phenotypes has to be exactly determined before genotypic resistance testing can be implemented in patient's care. Furthermore, the occurrence of cross-resistance is of utmost clinical importance. In this study, clinical HSV-1 isolates obtained between 2004 and 2011 from 26 patients after stem cell transplantation were examined in parallel by phenotypic and genotypic resistance testing. Thirteen isolates, which were phenotypically cross-resistant to acyclovir (ACV), penciclovir (PCV) and brivudin (BVDU), exhibited consistently frameshift or non-synonymous mutations in the TK gene known to confer resistance. One of these mutations (insertion of C at the nucleotide positions 1061-1065) has not been described before. Seven strains, phenotypically resistant to ACV and PCV and, except one each, sensitive to BVDU and resistant to foscarnet (FOS), carried uniformly resistance-related substitutions in the DNA pol gene. Finally, 3 isolates, resistant to ACV, PCV and 2 out of these also resistant to BVDU, had known but also unclear substitutions in the TK and DNA pol genes, and 3 isolates were completely sensitive. In conclusion, clinical ACV-resistant HSV-1 isolates, carrying resistance-associated mutations in the TK gene, can be regarded as cross-resistant to other nucleoside analogs such as BVDU. In contrast, clinical FOS-resistant HSV-1 strains which are cross-resistant to ACV may be sensitive to BVDU. This has to be considered for drug changes in antiviral treatment in case of ACV resistance.
authors.affiliation: Institute of Virology, German Reference Laboratory for CMV, University Hospital Ulm, Ulm, Germany.
authors.forename: Axel
authors.initials: A
authors.lastname: Schubert
authors.affiliation: Institute of Virology, German Reference Laboratory for CMV, University Hospital Ulm, Ulm, Germany; Institute for Experimental Cancer Research, University Hospital Ulm, Ulm, Germany.
authors.forename: Eva
authors.initials: E
authors.lastname: Gentner
authors.affiliation: Institute of Virology and Antiviral Therapy, German Reference Laboratory for HSV and VZV, Jena University Clinic, Jena, Germany.
authors.forename: Kathrin
authors.initials: K
authors.lastname: Bohn
authors.affiliation: Institute of Virology and Antiviral Therapy, German Reference Laboratory for HSV and VZV, Jena University Clinic, Jena, Germany.
authors.forename: Maximilian
authors.initials: M
authors.lastname: Schwarz
authors.affiliation: Institute of Virology, German Reference Laboratory for CMV, University Hospital Ulm, Ulm, Germany.
authors.forename: Thomas
authors.initials: T
authors.lastname: Mertens
authors.affiliation: Institute of Virology and Antiviral Therapy, German Reference Laboratory for HSV and VZV, Jena University Clinic, Jena, Germany. Electronic address: Andreas.Sauerbrei@med.uni-jena.de.
authors.forename: Andreas
authors.initials: A
authors.lastname: Sauerbrei
mesh_terms: D000212:Acyclovir / Q000031:analogs & derivatives / Q000494:pharmacology; D000293:Adolescent; D000328:Adult; D000368:Aged; D000998:Antiviral Agents / Q000494:pharmacology; D001973:Bromodeoxyuridine / Q000031:analogs & derivatives / Q000494:pharmacology; D002648:Child; D004279:DNA, Viral / Q000737:chemistry / Q000235:genetics; D004259:DNA-Directed DNA Polymerase / Q000235:genetics*; D024882:Drug Resistance, Viral; D005090:Exodeoxyribonucleases / Q000235:genetics*; D005260:Female; D016368:Frameshift Mutation; D006147:Guanine; D006561:Herpes Simplex / Q000821:virology*; D018259:Herpesvirus 1, Human / Q000187:drug effects* / Q000201:enzymology* / Q000235:genetics / Q000302:isolation & purification; D006801:Humans; D008297:Male; D008826:Microbial Sensitivity Tests; D008875:Middle Aged; D016254:Mutagenesis, Insertional; D020125:Mutation, Missense; D017354:Point Mutation; D020641:Polymorphism, Single Nucleotide; D017422:Sequence Analysis, DNA; D013937:Thymidine Kinase / Q000235:genetics*; D014764:Viral Proteins / Q000235:genetics*; D055815:Young Adult
chemical_list: D000998:Antiviral Agents; D004279:DNA, Viral; D014764:Viral Proteins; C020235:brivudine; C053539:penciclovir; D006147:Guanine; D013937:Thymidine Kinase; D004259:DNA-Directed DNA Polymerase; D005090:Exodeoxyribonucleases; C043417:DNA polymerase, Simplexvirus; D001973:Bromodeoxyuridine; D000212:Acyclovir
keywords: HSCT; HSV-1; Resistance genotype; Resistance phenotype