Most cases of herpes simplex virus 1 (HSV-1) encephalitis (HSE) remain unexplained^1,2. Here, we report on two unrelated people who had HSE as children and are homozygous for rare deleterious variants of TMEFF1, which encodes a cell membrane protein that is preferentially expressed by brain cortical neurons. TMEFF1 interacts with the cell-surface HSV-1 receptor NECTIN-1, impairing HSV-1 glycoprotein D- and NECTIN-1-mediated fusion of the virus and the cell membrane, blocking viral entry. Genetic TMEFF1 deficiency allows HSV-1 to rapidly enter cortical neurons that are either patient specific or derived from CRISPR–Cas9-engineered human pluripotent stem cells, thereby enhancing HSV-1 translocation to the nucleus and subsequent replication. This cellular phenotype can be rescued by pretreatment with type I interferon (IFN) or the expression of exogenous wild-type TMEFF1. Moreover, ectopic expression of full-length TMEFF1 or its amino-terminal extracellular domain, but not its carboxy-terminal intracellular domain, impairs HSV-1 entry into NECTIN-1-expressing cells other than neurons, increasing their resistance to HSV-1 infection. Human TMEFF1 is therefore a host restriction factor for HSV-1 entry into cortical neurons. Its constitutively high abundance in cortical neurons protects these cells from HSV-1 infection, whereas inherited TMEFF1 deficiency renders them susceptible to this virus and can therefore underlie HSE.

大多数单纯疱疹病毒 1 (HSV-1) 脑炎 (HSE) 病例仍无法解释^1,2 。在这里，我们报道了两名无关的人，他们在儿童时期患有 HSE，并且是TMEFF1罕见有害变体的纯合子，TMEFF1 编码一种优先由大脑皮层神经元表达的细胞膜蛋白。 TMEFF1 与细胞表面 HSV-1 受体 NECTIN-1 相互作用，损害 HSV-1 糖蛋白 D 和 NECTIN-1 介导的病毒与细胞膜的融合，从而阻止病毒进入。遗传性 TMEFF1 缺陷使 HSV-1 能够快速进入患者特异性或源自 CRISPR-Cas9 工程人类多能干细胞的皮层神经元，从而增强 HSV-1 向细胞核的易位和随后的复制。这种细胞表型可以通过用 I 型干扰素 (IFN) 预处理或表达外源野生型TMEFF1来挽救。此外，全长TMEFF1或其氨基末端胞外结构域（而非其羧基末端胞内结构域）的异位表达会损害HSV-1进入神经元以外的NECTIN-1表达细胞，从而增加它们对HSV-1感染的抵抗力。因此，人 TMEFF1 是 HSV-1 进入皮质神经元的宿主限制因子。它在皮质神经元中的组成性高丰度可以保护这些细胞免受 HSV-1 感染，而遗传性 TMEFF1 缺陷使它们对这种病毒敏感，因此可能成为 HSE 的基础。