New Mechanism of Acyclovir Resistance in Herpes Simplex Virus 1, Which Has a UAG Stop Codon between the First and Second AUG Initiation Codons

• Published in: Japanese Journal of Infectious Diseases Vol. 73; no. 6; pp. 447 - 451
• Main Authors: Nguyen, Phu Hoang Anh, Yamada, Souichi, Shibamura, Miho, Inagaki, Takuya, Fujii, Hikaru, Harada, Shizuko, Fukushi, Shuetsu, Mizuguchi, Masashi, Saijo, Masayuki
• Format: Journal Article
• Language: English
• Published: National Institute of Infectious Diseases, Japanese Journal of Infectious Diseases Editorial Committee 30.11.2020
• Subjects: acyclovir; amber mutation; herpes simplex virus 1; resistance; viral thymidine kinase
• ISSN: 1344-6304; 1884-2836; 1884-2836
• DOI: 10.7883/yoken.JJID.2020.313

Morphological changes in the structure of the herpes simplex virus 1 (HSV-1) viral thymidine kinase (vTK) polypeptide usually lead to conferring acyclovir (ACV) resistance. HSV-1 I4-2, in which a UAG stop codon is present at the 8th position between the 1st initiation AUG codon (1st position) and the 2nd initiation AUG codon (46th position) of the HSV-1 vTK gene, showed sensitivity to ACV. In contrast, HSV-1 KG111, in which a UAG stop codon was artificially inserted at the 44th position, showed resistance to ACV at 39˚C. The mechanism underlying the difference in the sensitivity profiles was elucidated. The virus recombinants HSV-1-TK(8UAG) and HSV-1-TK(44UAG) containing a UAG stop codon at the 8th and 44th positions counted from the 1st initiation codon, respectively, were generated and tested for susceptibility to antiviral compounds. HSV-1-TK(8UAG) and HSV-1-TK(44UAG) were sensitive and resistant to ACV and BVdU at 37˚C, respectively. The expression level of the truncated vTK translated from the 2nd initiation codon in Vero cells infected with HSV-1-TK(44UAG) was clearly less than that with HSV-1-TK(8UAG) in a temperature-dependent manner. The differences in the antiviral sensitivity profiles were due to the position of the UAG stop codon between the 1st and the 2nd initiation codons.