Association between sensitivity of viral thymidine kinase-associated acyclovir-resistant herpes simplex virus type 1 and virulence

• Published in: Virology journal Vol. 14; no. 1; p. 59
• Main Authors: Omura, Natsumi, Fujii, Hikaru, Yoshikawa, Tomoki, Yamada, Souichi, Harada, Shizuko, Inagaki, Takuya, Shibamura, Miho, Takeyama, Haruko, Saijo, Masayuki
• Format: Journal Article
• Language: English
• Published: England BioMed Central 21.03.2017
• Subjects: Acyclovir; Acyclovir - pharmacology; Amino acid substitution; Animals; Antiviral Agents - pharmacology; Antiviral drugs; clones; Cloning; Cornea; Deoxyribonucleic acid; Dermatitis; Disease Models, Animal; DNA; Drug resistance; Drug Resistance, Viral; Experiments; Female; Genes; Herpes simplex; Herpes Simplex - pathology; Herpes Simplex - virology; Herpes viruses; Herpesvirus 1, Human - drug effects; Herpesvirus 1, Human - enzymology; Herpesvirus 1, Human - genetics; Herpesvirus 1, Human - pathogenicity; Human alphaherpesvirus 1; Immunocompromised hosts; Infections; inhibitory concentration 50; Keratitis; Kinases; Lethal dose; lethal dose 50; mice; Mice, Inbred BALB C; Mutant Proteins - genetics; Mutation; Pathogenesis; patients; Penicillin; Statistical analysis; Thymidine; Thymidine kinase; Thymidine Kinase - genetics; Virulence; Resistance; Thymidine kinase; Herpes simplex virus type 1; Acyclovir; Virulence
• ISSN: 1743-422X; 1743-422X
• DOI: 10.1186/s12985-017-0728-2

Acyclovir (ACV)-resistant (ACVr) herpes simplex virus type 1 (HSV-1) infections are concern in immunocompromised patients. Most clinical ACVr HSV-1 isolates have mutations in the viral thymidine kinase (vTK) genes. The vTK-associated ACVr HSV-1 shows reduced virulence, but the association between the level of resistance and the virulence of the vTK-associated ACVr HSV-1 is still unclear. The virulence in mice of 5 vTK-associated ACVr HSV-1 clones with a variety of ACV sensitivities, when inoculated through intracerebral and corneal routes, was evaluated in comparison with ACV-sensitive (ACVs) parent HSV-1 TAS. Although all the 5 ACVr HSV-1 clones and ACVs HSV-1 TAS showed a similar single-step growth capacity in vitro, the virulence of ACVr HSV-1 clones significantly decreased. A 50% lethal dose (LD ) of each clone was closely correlated with 50% inhibitory concentrations (IC ), demonstrating that the higher the ACV-sensitvity, the the higher the virulence among the ACVr clones. One of the ACVr HSV-1 clones with a relatively low IC value maintained similar virulence to that of the parent TAS. The infection in mice with ACVr HSV-1 due to a single amino acid substitution in vTK induced local diseases, keratitis and dermatitis, while vTK-deficient clone did not. A statistically significant correlation between the virulence and susceptibility to ACV among ACVr HSV-1 clones was demonstrated.