R9AP is a functional receptor for Epstein-Barr virus infection in both epithelial cells and B cells

Abstract Epstein-Barr virus (EBV), also known as the first human tumor virus, is linked to about 200,000 new cancer cases and millions of non-malignant diseases every year. EBV infects both human epithelial cells and B cells. Several virally encoded glycoproteins define tropism and mediate a complicated entry process. Here, we show that in both epithelial cells and B cells, R9AP silencing or genetic knockout significantly inhibits EBV infection, whereas R9AP overexpression promotes EBV infection, establishing R9AP as an essential entry receptor for EBV. Mechanistically, R9AP directly binds to EBV glycoproteins gH/gL to mediate membrane fusion. Importantly, the interaction of R9AP with gH/gL is inhibited by the highly potent, competitive gH/gL neutralizing antibody AMMO1 that blocks EBV infection of both epithelial cells and B cells. Furthermore, a R9AP peptide encompassing the gH/gL binding site inhibits EBV infection in vitro and reduces viral load in EBV infected humanized mice. Altogether, we propose R9AP as the first characterized receptor for EBV infection common to epithelial cells and B cells and a potential target for intervention.