The brain is highly sensitive to damage caused by infection and inflammation^1,2. Herpes simplex virus 1 (HSV-1) is a neurotropic virus and the cause of herpes simplex encephalitis³. It is unknown whether neuron-specific antiviral factors control virus replication to prevent infection and excessive inflammatory responses, hence protecting the brain. Here we identify TMEFF1 as an HSV-1 restriction factor using genome-wide CRISPR screening. TMEFF1 is expressed specifically in neurons of the central nervous system and is not regulated by type I interferon, the best-known innate antiviral system controlling virus infections. Depletion of TMEFF1 in stem-cell-derived human neurons led to elevated viral replication and neuronal death following HSV-1 infection. TMEFF1 blocked the HSV-1 replication cycle at the level of viral entry through interactions with nectin-1 and non-muscle myosin heavy chains IIA and IIB, which are core proteins in virus–cell binding and virus–cell fusion, respectively^4,5,6. Notably, Tmeff1^−/− mice exhibited increased susceptibility to HSV-1 infection in the brain but not in the periphery. Within the brain, elevated viral load was observed specifically in neurons. Our study identifies TMEFF1 as a neuron-specific restriction factor essential for prevention of HSV-1 replication in the central nervous system.

大脑对感染和炎症造成的损伤高度敏感^1,2 。单纯疱疹病毒 1 (HSV-1) 是一种嗜神经病毒，是单纯疱疹脑炎的病因³ 。目前尚不清楚神经元特异性抗病毒因子是否控制病毒复制以防止感染和过度炎症反应，从而保护大脑。在这里，我们使用全基因组 CRISPR 筛选将 TMEFF1 鉴定为 HSV-1 限制因子。 TMEFF1 在中枢神经系统的神经元中特异性表达，不受 I 型干扰素（控制病毒感染的最著名的先天抗病毒系统）的调节。 HSV-1 感染后，干细胞来源的人类神经元中 TMEFF1 的缺失导致病毒复制增加和神经元死亡。 TMEFF1 通过与 nectin-1 和非肌肉肌球蛋白重链 IIA 和 IIB 相互作用，在病毒进入水平阻断 HSV-1 复制周期，它们分别是病毒-细胞结合和病毒-细胞融合的核心蛋白^{4,5 ,6} .值得注意的是， Tmeff1 ^−/−小鼠的大脑对 HSV-1 感染的易感性增加，但外周却没有增加。在大脑内，特别是在神经元中观察到病毒载量升高。我们的研究确定 TMEFF1 是一种神经元特异性限制因子，对于预防中枢神经系统中的 HSV-1 复制至关重要。