Association between sensitivity of viral thymidine kinase-associated acyclovir-resistant herpes simplex virus type 1 and virulence.
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 (LD50) of each clone was closely correlated with 50% inhibitory concentrations (IC50), 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 IC50value 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.
Department of Virology 1, National Institute of Infectious Diseases, 1-23-1 Toyama, Shinjuku-ku, Tokyo, 162-8640, Japan.|Department of Life Science and Medical Bioscience, Waseda University, 2-2 Wakamatsu-cho, Shinjuku-ku, Tokyo, Japan.
Natsumi
N
Omura
Department of Virology 1, National Institute of Infectious Diseases, 1-23-1 Toyama, Shinjuku-ku, Tokyo, 162-8640, Japan.
Hikaru
H
Fujii
Department of Virology 1, National Institute of Infectious Diseases, 1-23-1 Toyama, Shinjuku-ku, Tokyo, 162-8640, Japan.
Tomoki
T
Yoshikawa
Department of Virology 1, National Institute of Infectious Diseases, 1-23-1 Toyama, Shinjuku-ku, Tokyo, 162-8640, Japan.
Souichi
S
Yamada
Department of Virology 1, National Institute of Infectious Diseases, 1-23-1 Toyama, Shinjuku-ku, Tokyo, 162-8640, Japan.
Shizuko
S
Harada
Department of Virology 1, National Institute of Infectious Diseases, 1-23-1 Toyama, Shinjuku-ku, Tokyo, 162-8640, Japan.|Department of Life Science and Medical Bioscience, Waseda University, 2-2 Wakamatsu-cho, Shinjuku-ku, Tokyo, Japan.
Takuya
T
Inagaki
Department of Virology 1, National Institute of Infectious Diseases, 1-23-1 Toyama, Shinjuku-ku, Tokyo, 162-8640, Japan.
Miho
M
Shibamura
Department of Life Science and Medical Bioscience, Waseda University, 2-2 Wakamatsu-cho, Shinjuku-ku, Tokyo, Japan.
Haruko
H
Takeyama
Department of Virology 1, National Institute of Infectious Diseases, 1-23-1 Toyama, Shinjuku-ku, Tokyo, 162-8640, Japan. msaijo@nih.go.jp.|Department of Life Science and Medical Bioscience, Waseda University, 2-2 Wakamatsu-cho, Shinjuku-ku, Tokyo, Japan. msaijo@nih.go.jp.
Masayuki
M
Saijo
D000212:Acyclovir / Q000494:pharmacology*; D000818:Animals; D000998:Antiviral Agents / Q000494:pharmacology*; D004195:Disease Models, Animal; D024882:Drug Resistance, Viral; D005260:Female; D006561:Herpes Simplex / Q000473:pathology* / Q000821:virology; D018259:Herpesvirus 1, Human / Q000187:drug effects* / Q000201:enzymology / Q000235:genetics / Q000472:pathogenicity*; D008807:Mice, Inbred BALB C; D050505:Mutant Proteins / Q000235:genetics; D013937:Thymidine Kinase / Q000235:genetics*; D014774:Virulence
D000998:Antiviral Agents; D050505:Mutant Proteins; D013937:Thymidine Kinase; D000212:Acyclovir
Acyclovir; Herpes simplex virus type 1; Resistance; Thymidine kinase; Virulence