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

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.

Citation

Phu Hoang Anh Nguyen, Souichi Yamada, Miho Shibamura, Takuya Inagaki, Hikaru Fujii, Shizuko Harada, Shuetsu Fukushi, Masashi Mizuguchi, Masayuki Saijo. New Mechanism of Acyclovir Resistance in Herpes Simplex Virus 1, Which Has a UAG Stop Codon between the First and Second AUG Initiation Codons. Japanese journal of infectious diseases. 2020 Nov 24;73(6):447-451

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PMID: 32611982

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