Human TMEFF1 is a restriction factor for 1 herpes simplex virus in the brain

Most cases of herpes simplex virus-1 (HSV-1) encephalitis (HSE) remain unexplained. We report two unrelated children with HSE homozygous for rare deleterious variants of TMEFF1, which encodes a cell membrane protein preferentially expressed by brain cortical neurons. On the cell surface, TMEFF1 interacts with the HSV-1 receptor NECTIN-1, impairing HSV-1 glycoprotein D (gD)-human NECTIN-1-mediated virus-cell membrane fusion and viral entry. Genetic TMEFF1 deficiency allows HSV-1 to enter patient-specific or CRISPR-Cas9-engineered human pluripotent stem cell (hPSC)-derived cortical neurons rapidly, thereby enhancing HSV-1 translocation to the nucleus and replication. This cellular phenotype can be rescued by pretreatment with type I IFN or the expression of exogenous wild-type TMEFF1. Moreover, ectopic expression of the full-length TMEFF1 or its N-terminal extracellular domain, but not its C-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, thus, 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 underlies HSE.