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Here, we report on two unrelated people who had HSE as children and are homozygous for rare deleterious variants of\n                    <jats:italic>TMEFF1<\/jats:italic>\n                    , which encodes a cell\u00a0membrane 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\u2013Cas9-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\n                    <jats:italic>TMEFF1<\/jats:italic>\n                    . 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.\n                  <\/jats:p>","DOI":"10.1038\/s41586-024-07745-x","type":"journal-article","created":{"date-parts":[[2024,7,24]],"date-time":"2024-07-24T12:01:55Z","timestamp":1721822515000},"page":"390-400","update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":31,"title":["Human TMEFF1 is a restriction factor for herpes simplex virus in the 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