Virulence of herpes simplex virus 1 harbouring a UAG stop codon between the first and second initiation codon in the thymidine kinase gene

Abstract

Herpes simplex virus 1 (HSV-1)-TK(8UAG) expresses a truncated thymidine kinase (TK) translated from the second initiation codon due to a stop UAG codon at the 8th position (counted from the first initiation codon). Here, we showed that the sensitivity of HSV-1-TK(8UAG) to acyclovir (ACV) is similar to that of control HSV-1 wild-type (WT), which expresses an intact TK protein. However, HSV-1-TK(44UAG), which expresses a truncated TK due to a UAG codon at position 44, showed lower sensitivity to ACV. A mouse infection model was used to compare the virulence of HSV-1-TK(8UAG) and HSV-1-TK(44UAG) with that of HSV-1 wild-type (WT). The 50% lethal dose (LD₅₀) value of HSV-1-TK(44UAG) was 7.8-fold higher than that of HSV-1-TK(8UAG), whereas the LD₅₀ value of HSV-1-TK(8UAG) was the same as that of the parental HSV-1 WT. There were no statistically significant differences between HSV-1-TK(44UAG), HSV-1-TK(8UAG), and HSV-1 WT with respect to replication capacity and viral TK mRNA expression in mouse brain. Thus, the virulence of HSV-1 expressing a truncated viral TK translated from the second initiation codon might depend on the position of the UAG stop codon.