A Mutation in the Herpes Simplex Virus Type 1 (HSV-1) UL29 Gene is Associated with Anti-Herpesvirus Drugs’ Susceptibility

• Published in: Viruses Vol. 16; no. 12; p. 1813
• Main Authors: Yamada, Souichi, Harada, Shizuko, Fujii, Hikaru, Kinoshita, Hitomi, Nguyen, Phu Hoang Anh, Shibamura, Miho, Yoshikawa, Tomoki, Kawahara, Madoka, Ebihara, Hideki, Saijo, Masayuki, Fukushi, Shuetsu
• Format: Journal Article
• Language: English
• Published: Switzerland MDPI AG 01.12.2024; MDPI
• Subjects: Acyclovir; Acyclovir - pharmacology; Acyclovir - therapeutic use; Animals; Antiviral Agents - pharmacology; Antiviral Agents - therapeutic use; Antiviral drugs; Chemicals; Chlorocebus aethiops; Cloning; Disease resistance; DNA-Binding Proteins - genetics; DNA-Binding Proteins - metabolism; DNA-directed DNA polymerase; DNA-Directed DNA Polymerase - genetics; DNA-Directed DNA Polymerase - metabolism; Drug resistance; Drug resistance in microorganisms; Drug Resistance, Viral - genetics; E coli; Gene mutations; Genes; Genes, Viral; Genetic aspects; Genomes; Health aspects; Herpes simplex; Herpes Simplex - drug therapy; Herpes Simplex - virology; Herpes simplex virus; herpes simplex virus type 1 (HSV-1); Herpes viruses; Herpesvirus 1, Human - drug effects; Herpesvirus 1, Human - genetics; Humans; ICP8 protein; Infections; Kinases; Microbial Sensitivity Tests; Missense mutation; Mutagenesis; Mutants; Mutation; Mutation, Missense; Penicillin; Polyclonal antibodies; Proteins; Thymidine kinase; Thymidine Kinase - genetics; Thymidine Kinase - metabolism; UL29; Varicella; Vero Cells; Viral Proteins - genetics; Viral Proteins - metabolism; Whole genome sequencing; Japan; St Louis Missouri; United Kingdom > UK; United States > US; Germany; UL29; acyclovir; drug resistance; herpes simplex virus type 1 (HSV-1)
• DOI: 10.3390/v16121813
• ISSN: 1999-4915

Herpes simplex virus type 1 (HSV-1) acyclovir (ACV) resistance is acquired by mutations in the viral thymidine kinase (TK) or DNA polymerase (DNApol) genes. We previously obtained an ACV-resistant clone (HSV-1_VZV_TK_clone α) by sequential passages of HSV-1_VZV-TK, a recombinant virus which lacked its endogenous TK activity and instead expressed the varicella-zoster virus (VZV) TK ectopically. HSV-1_VZV_TK_clone α had been generated using an HSV-1_BAC in the presence of increasing concentrations of ACV. The ACV-resistant clone bore normal TK and DNApol genes. Here, we deployed next-generation full-genome sequencing of HSV-1_VZV_TK_clone α and identified a single nucleotide substitution, resulting in a P597L missense mutation in the UL29 gene product, the ICP8 protein. Recombinant HSV-1 encoding a P597L ICP8 protein was generated, and its properties and ability to confer drug resistance were analyzed. No difference in virus growth and UL29 expression was observed between the mutant recombinant, the wild type, and a revertant mutant viral strain, and susceptibility tests of these strains to ACV and other drugs using Vero, HEL, and ARPE19 cells identified that the recombinant UL29 mutant virus was resistant only to ACV. These results indicate that ICP8 may be involved in the anti-herpesvirus drugs’ mechanism of action on HSV-1.