Attenuated neurovirulence of dUTPase-deficient herpes simplex virus type 1 in suckling mice but not in newborn mice

The HSV-1 UL50 gene encodes dUTPase (DUT), which dephosphorylates dUTP into dUMP, and its mutant strain is known to reduce neurovirulence in mice over 3 weeks old. Therefore, the UL50-deficient strain may be a candidate as a vaccine strain or viral vector. In this study, the UL50-deficient strain demonstrated reduced levels of replication in brain and neurovirulence compared to the wild strain in 4-week-old mice, but not in newborn mice. Furthermore, the expression level of cellular DUT in the mouse brain was not detectable in 4-week-old mice, but was detectable in newborn mice. In vitro experiments showed replication of the UL50-deficient strain was reduced due to the knockdown of cellular DUT. These results suggest that in actively dividing cells, such as the brain neurons of newborn mice, efficient cellular DUT expression helps with the sufficient replication of the UL50 mutant, resulting in the same level of neurovirulence as that in the wild type. However, in the brains of 4-week-old mice, DUT expression is insufficient, resulting in reduced neurovirulence of the UL50 mutant. These results suggest that when using the UL50 mutant strain as a vaccine or virus vector, it is necessary to pay attention to the timing of inoculation.