TY - JOUR
T1 - Acyclovir sensitivity and neurovirulence of herpes simplex virus type 1 with amino acid substitutions in the viral thymidine kinase gene, which were detected in the patients with intractable herpes simplex encephalitis previously reported
AU - Inagaki, Takuya
AU - Satoh, Masaaki
AU - Fujii, Hikaru
AU - Yamada, Souichi
AU - Shibamura, Miho
AU - Yoshikawa, Tomoki
AU - Harada, Shizuko
AU - Takeyama, Haruko
AU - Saijo, Masayuki
N1 - Funding Information:
We appreciate Dr. Yasushi Kawaguchi, who kindly provided us with HSV-1 F, E. coli GS1783 containing pYEbac102, and a plasmid pEP-kanS, and we also appreciate Dr. Bernard Roizman, Dr. Gregory A. Smith, and Dr. Nikolaus Oster-rieder to give the permission for it. We thank Ms. Yoshiko Fukui and Ms. Mihoko Tsuda for their assistance in this work. This work was financially supported by Grants-in-Aid for Scientific Research from the Japan Society for the Promotion of Science (Nos. 15K09675, 24591591, and 18K07894), and a grant from the Japan Foundation for Pediatric Research (Grant No. 14-015).
PY - 2018
Y1 - 2018
N2 - Several cases of herpes simplex encephalitis (HSE) caused by acyclovir (ACV)-resistant herpes simplex virus type 1 (HSV-1) have been reported. Amino acid substitutions of R41H, Q125H, and A156V in the viral thymidine kinase (vTK) gene have been reported to confer ACV resistance. Recombinant HSV-1 clones, containing each amino acid substitution in the vTK gene, were generated using the bacterial artificial chromosome system. A recombinant HSV-1 with the Q125H substitution showed ACV resistance while the R41H or A156V substitutions were ACV-sensitive. Furthermore, the Q125H recombinant HSV-1 was less virulent than the repaired virus, but it maintained neurovirulence in mice at relatively high levels. Substitution of Q125H, which was detected in the neonatal HSE patient, conferred ACV resistance, but the substitutions of R41H and A156V, which were detected in immunocompetent adult HSE patients, did not. This suggests that HSE caused by ACV-resistant HSV-1 might be a very rare event to occur during the course of ACV treatment in immunocompetent patients. Showing resistance to ACV treatment does not always indicate emergence of ACV-resistant HSV-1 in HSE patients.
AB - Several cases of herpes simplex encephalitis (HSE) caused by acyclovir (ACV)-resistant herpes simplex virus type 1 (HSV-1) have been reported. Amino acid substitutions of R41H, Q125H, and A156V in the viral thymidine kinase (vTK) gene have been reported to confer ACV resistance. Recombinant HSV-1 clones, containing each amino acid substitution in the vTK gene, were generated using the bacterial artificial chromosome system. A recombinant HSV-1 with the Q125H substitution showed ACV resistance while the R41H or A156V substitutions were ACV-sensitive. Furthermore, the Q125H recombinant HSV-1 was less virulent than the repaired virus, but it maintained neurovirulence in mice at relatively high levels. Substitution of Q125H, which was detected in the neonatal HSE patient, conferred ACV resistance, but the substitutions of R41H and A156V, which were detected in immunocompetent adult HSE patients, did not. This suggests that HSE caused by ACV-resistant HSV-1 might be a very rare event to occur during the course of ACV treatment in immunocompetent patients. Showing resistance to ACV treatment does not always indicate emergence of ACV-resistant HSV-1 in HSE patients.
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U2 - 10.7883/yoken.JJID.2018.176
DO - 10.7883/yoken.JJID.2018.176
M3 - Article
C2 - 29848849
AN - SCOPUS:85056992472
VL - 71
SP - 343
EP - 349
JO - Japanese Journal of Infectious Diseases
JF - Japanese Journal of Infectious Diseases
SN - 1344-6304
IS - 5
ER -