Kato Akihisa, Harima Hayato, Tsunekawa Yuji, Igarashi Manabu, Kitamura Kouichi, Wakae Kousho, Nishiyama Tomoaki, Morimoto Satoru, Suzuki Toru, Kozuka-Hata Hiroko, Oyama Masaaki, Motooka Daisuke, Watanabe Mizuki, Takeshima Kousuke, Maruzuru Yuhei, Koyanagi Naoto, Okano Hideyuki, Inada Toshifumi, Okada Takashi, Muramatsu Masamichi, Kawaguchi Yasushi
Division of Molecular Virology, Department of Microbiology and Immunology, The Institute of Medical Science, The University of Tokyo, Tokyo, Japan.
Department of Infectious Disease Control, International Research Center for Infectious Diseases, The Institute of Medical Science, The University of Tokyo, Tokyo, Japan.
Nat Microbiol. 2025 Jun 3. doi: 10.1038/s41564-025-02026-3.
Herpes simplex virus 1 (HSV-1) is the most common cause of viral encephalitis, which can be lethal or result in severe neurological defects despite antiviral therapy. The apolipoprotein B messenger-RNA editing enzyme, catalytic polypeptide-like (APOBEC) group of proteins can act as viral restriction factors. How HSV-1 evades this intrinsic immune mechanism is unclear. Here, using human carcinoma HEp-2 cells, we find that phosphorylation and therefore activation of HSV-1 uracil-DNA glycosylase counteracts mouse APOBEC1 DNA-editing activity on HSV-1 genomes. This protects viral genomes, promotes viral replication and encephalitis in the central nervous system of mice. Presence of Apobec1 improved encephalitis outcomes in mice challenged with HSV-1 carrying a mutation in the phosphorylation site of uracil-DNA glycosylase. Treatment with an UNG inhibitor, adeno-associated virus vector expressing UGI, protected wild-type HSV-1-infected mice from lethal encephalitis. These findings identify uracil-DNA glycosylase as a viral factor enabling evasion from intrinsic antiviral immunity mediated by APOBEC1 in the central nervous system and suggests a potential therapeutic approach to treat HSV-1 encephalitis.
单纯疱疹病毒1型（HSV-1）是病毒性脑炎最常见的病因，尽管进行了抗病毒治疗，仍可能致命或导致严重的神经功能缺陷。载脂蛋白B信使核糖核酸编辑酶催化多肽样（APOBEC）蛋白家族可作为病毒限制因子。HSV-1如何逃避这种固有免疫机制尚不清楚。在此，我们利用人癌细胞系HEp-2细胞发现，HSV-1尿嘧啶-DNA糖基化酶的磷酸化及由此激活可抵消小鼠APOBEC1对HSV-1基因组的DNA编辑活性。这保护了病毒基因组，促进了病毒复制及小鼠中枢神经系统的脑炎发生。Apobec1的存在改善了感染携带尿嘧啶-DNA糖基化酶磷酸化位点突变的HSV-1的小鼠的脑炎结局。用UNG抑制剂（表达UGI的腺相关病毒载体）治疗可保护野生型HSV-1感染的小鼠免于致命性脑炎。这些发现确定尿嘧啶-DNA糖基化酶是一种病毒因子，可使其在中枢神经系统逃避由APOBEC1介导的固有抗病毒免疫，并提示了一种治疗HSV-1脑炎的潜在治疗方法。
