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

Natsumi Omura, Hikaru Fujii, Tomoki Yoshikawa, Souichi Yamada, Shizuko Harada, Takuya Inagaki, Miho Shibamura, Haruko Takeyama, Masayuki Saijo

    Research output: Contribution to journalArticle

    5 Citations (Scopus)

    Abstract

    Background: 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. Methods: 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. Results: 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 IC50 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. Conclusions: A statistically significant correlation between the virulence and susceptibility to ACV among ACVr HSV-1 clones was demonstrated.

    Original languageEnglish
    Article number59
    JournalVirology Journal
    Volume14
    Issue number1
    DOIs
    Publication statusPublished - 2017 Mar 21

    Fingerprint

    Acyclovir
    Thymidine Kinase
    Human Herpesvirus 1
    Virulence
    Clone Cells
    Inhibitory Concentration 50
    Lethal Dose 50
    Keratitis
    Immunocompromised Host
    Dermatitis
    Virus Diseases
    Amino Acid Substitution

    Keywords

    • Acyclovir
    • Herpes simplex virus type 1
    • Resistance
    • Thymidine kinase
    • Virulence

    ASJC Scopus subject areas

    • Infectious Diseases
    • Virology

    Cite this

    Association between sensitivity of viral thymidine kinase-associated acyclovir-resistant herpes simplex virus type 1 and virulence. / Omura, Natsumi; Fujii, Hikaru; Yoshikawa, Tomoki; Yamada, Souichi; Harada, Shizuko; Inagaki, Takuya; Shibamura, Miho; Takeyama, Haruko; Saijo, Masayuki.

    In: Virology Journal, Vol. 14, No. 1, 59, 21.03.2017.

    Research output: Contribution to journalArticle

    Omura, Natsumi ; Fujii, Hikaru ; Yoshikawa, Tomoki ; Yamada, Souichi ; Harada, Shizuko ; Inagaki, Takuya ; Shibamura, Miho ; Takeyama, Haruko ; Saijo, Masayuki. / Association between sensitivity of viral thymidine kinase-associated acyclovir-resistant herpes simplex virus type 1 and virulence. In: Virology Journal. 2017 ; Vol. 14, No. 1.
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    abstract = "Background: 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. Methods: 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. Results: 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 IC50 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. Conclusions: A statistically significant correlation between the virulence and susceptibility to ACV among ACVr HSV-1 clones was demonstrated.",
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    author = "Natsumi Omura and Hikaru Fujii and Tomoki Yoshikawa and Souichi Yamada and Shizuko Harada and Takuya Inagaki and Miho Shibamura and Haruko Takeyama and Masayuki Saijo",
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    T1 - Association between sensitivity of viral thymidine kinase-associated acyclovir-resistant herpes simplex virus type 1 and virulence

    AU - Omura, Natsumi

    AU - Fujii, Hikaru

    AU - Yoshikawa, Tomoki

    AU - Yamada, Souichi

    AU - Harada, Shizuko

    AU - Inagaki, Takuya

    AU - Shibamura, Miho

    AU - Takeyama, Haruko

    AU - Saijo, Masayuki

    PY - 2017/3/21

    Y1 - 2017/3/21

    N2 - Background: 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. Methods: 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. Results: 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 IC50 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. Conclusions: A statistically significant correlation between the virulence and susceptibility to ACV among ACVr HSV-1 clones was demonstrated.

    AB - Background: 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. Methods: 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. Results: 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 IC50 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. Conclusions: A statistically significant correlation between the virulence and susceptibility to ACV among ACVr HSV-1 clones was demonstrated.

    KW - Acyclovir

    KW - Herpes simplex virus type 1

    KW - Resistance

    KW - Thymidine kinase

    KW - Virulence

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    U2 - 10.1186/s12985-017-0728-2

    DO - 10.1186/s12985-017-0728-2

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