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Significance For achieving efficient entry into host cells, viruses utilize multiple host factors for mediating the stepwise entry process. Sole expression of sodium taurocholate cotransporting polypeptide (NTCP), a cellular receptor for hepatitis B virus (HBV), is not sufficient for the efficient viral internalization into hepatocytes. Here, we identify epidermal growth factor receptor (EGFR) as a host factor that interacts with NTCP and mediates HBV internalization. Dissociation of the NTCP–EGFR interaction or functional depletion of EGFR attenuated the viral internalization to NTCP-expressing cells and infection. Our data suggest that HBV enters human hepatocytes using an intrinsic NTCP–EGFR complex as a driving force. EGFR is thus an entry cofactor required for HBV infection of the human liver.

Epidermal growth factor receptor is a host-entry cofactor triggering hepatitis B virus internalization